Non-invasive nerve stimulation to treat or prevent autism spectrum disorders and other disorders of psychological development

ABSTRACT

Devices, systems and methods are disclosed for treating or preventing an autism spectrum disorder, a pervasive developmental disorder, or a disorder of psychological development. The methods comprise transmitting impulses of energy non-invasively to selected nerve fibers, particularly those in a vagus nerve. The nerve stimulation may be used as a behavior conditioning tool, by producing euphoria in an autistic individual. Vagus nerve stimulation is also used to modulate circulating serotonin levels in a pregnant woman so as to reduce the risk of having an autistic child; modulate the levels of growth factors within a child; promote balance of neuronal excitation/inhibition; modulate the activity of abnormal resting state neuronal networks; increase respiratory sinus arrhythmia; and avert episodes of motor stereotypies with the aid of forecasting methods.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. Nonprovisional application Ser.No. 13/783,319 filed Mar. 3, 2013; which is a Continuation-in-Part ofU.S. Nonprovisional application Ser. No. 13/731,035 filed Dec. 30, 2012,now U.S. Pat. No. 9,403,001 issued Aug. 2, 2016; which is aContinuation-in-Part of U.S. Nonprovisional application Ser. No.13/603,781 filed Sep. 5, 2012, now U.S. Pat. No. 8,983,628 issued Mar.17, 2015; which is a Continuation-in-Part of U.S. Nonprovisionalapplication Ser. No. 13/222,087 filed Aug. 31, 2011, now U.S. Pat. No.9,174,066 issued Nov. 3, 2015; which is a Continuation-in-Part of U.S.Nonprovisional application Ser. No. 13/183,765 filed Jul. 15, 2011, nowU.S. Pat. No. 8,874,227 issued Oct. 28, 2014; which (a) claims thebenefit of U.S. Provisional Application Ser. No. 61/488,208 filed May20, 2011; and (b) is a Continuation-in-Part of U.S. Nonprovisionalapplication Ser. No. 13/183,721 filed Jul. 15, 2011, now U.S. Pat. No.8,676,324 issued Mar. 18, 2014; which (a) claims the benefit of U.S.Provisional Application Ser. No. 61/487,439 filed May 18, 2011; and (b)is a Continuation-in-Part of U.S. Nonprovisional application Ser. No.13/109,250 filed May 17, 2011, now U.S. Pat. No. 8,676,330 issued Mar.18, 2014; which (a) claims the benefit of U.S. Provisional ApplicationSer. No. 61/471,405 filed Apr. 4, 2011; and (b) is aContinuation-in-Part of U.S. Nonprovisional application Ser. No.13/075,746 filed Mar. 30, 2011, now U.S. Pat. No. 8,874,205 issued Oct.28, 2014; which (a) claims the benefit of U.S. Provisional ApplicationSer. No. 61/451,259 filed Mar. 10, 2011; and (b) is aContinuation-in-Part of U.S. Nonprovisional application Ser. No.13/005,005 filed Jan. 12, 2011, now U.S. Pat. No. 8,868,177 issued Oct.21, 2014; which is a Continuation-in-Part of U.S. Nonprovisionalapplication Ser. No. 12/964,050 filed Dec. 9, 2010; which claims thebenefit of U.S. Provisional Application Ser. No. 61/415,469 filed Nov.19, 2010, each of which is incorporated herein by reference in itsentirety for all purposes.

BACKGROUND OF THE INVENTION

The field of the present invention relates to the delivery of energyimpulses (and/or fields) to bodily tissues for therapeutic purposes. Theinvention relates more specifically to devices and methods for treatingconditions associated with autism and other disorders of psychologicaldevelopment. The energy impulses (and/or fields) that are used to treatthose conditions comprise electrical and/or electromagnetic energy,delivered non-invasively to the patient.

The use of electrical stimulation for treatment of medical conditions iswell known. For example, electrical stimulation of the brain withimplanted electrodes (deep brain stimulation) has been approved for usein the treatment of various conditions, including pain and movementdisorders such as essential tremor and Parkinson's disease [Joel S.PERLMUTTER and Jonathan W. Mink. Deep brain stimulation. Annu. Rev.Neurosci 29 (2006):229-257].

Another application of electrical stimulation of nerves is the treatmentof radiating pain in the lower extremities by stimulating the sacralnerve roots at the bottom of the spinal cord [Paul F. WHITE, Shitong Liand Jen W. Chiu. Electroanalgesia: Its Role in Acute and Chronic PainManagement. Anesth Analg 92(2001):505-513; U.S. Pat. No. 6,871,099,entitled Fully implantable microstimulator for spinal cord stimulationas a therapy for chronic pain, to WHITEHURST, et al].

The form of electrical stimulation that is most relevant to the presentinvention is vagus nerve stimulation (VNS, also known as vagal nervestimulation). It was developed initially for the treatment of partialonset epilepsy and was subsequently developed for the treatment ofdepression and other disorders. The left vagus nerve is ordinarilystimulated at a location within the neck by first surgically implantingan electrode there and then connecting the electrode to an electricalstimulator [U.S. Pat. No. 4,702,254 entitled Neurocybernetic prosthesis,to ZABARA; U.S. Pat. No. 6,341,236 entitled Vagal nerve stimulationtechniques for treatment of epileptic seizures, to OSORIO et al;US5299569 entitled Treatment of neuropsychiatric disorders by nervestimulation, to WERNICKE et al; G. C. ALBERT, C. M. Cook, F. S. Prato,A. W. Thomas. Deep brain stimulation, vagal nerve stimulation andtranscranial stimulation: An overview of stimulation parameters andneurotransmitter release. Neuroscience and Biobehavioral Reviews 33(2009):1042-1060; GROVES D A, Brown V J. Vagal nerve stimulation: areview of its applications and potential mechanisms that mediate itsclinical effects. Neurosci Biobehav Rev 29(2005):493-500; Reese TERRY,Jr. Vagus nerve stimulation: a proven therapy for treatment of epilepsystrives to improve efficacy and expand applications. Conf Proc IEEE EngMed Biol Soc. 2009; 2009:4631-4634; Timothy B. MAPSTONE. Vagus nervestimulation: current concepts. Neurosurg Focus 25 (3, 2008):E9, pp. 1-4;ANDREWS, R. J. Neuromodulation. I. Techniques-deep brain stimulation,vagus nerve stimulation, and transcranial magnetic stimulation. Ann. N.Y. Acad. Sci. 993(2003):1-13; LABINER, D. M., Ahern, G. L. Vagus nervestimulation therapy in depression and epilepsy: therapeutic parametersettings. Acta. Neurol. Scand. 115(2007):23-33].

Many such therapeutic applications of electrical stimulation involve thesurgical implantation of electrodes within a patient. In contrast,devices used for the procedures that are disclosed here do not involvesurgery. Instead, the present devices and methods stimulate nerves bytransmitting energy to nerves and tissue non-invasively. A medicalprocedure is defined as being non-invasive when no break in the skin (orother surface of the body, such as a wound bed) is created through useof the method, and when there is no contact with an internal body cavitybeyond a body orifice (e.g, beyond the mouth or beyond the externalauditory meatus of the ear). Such non-invasive procedures aredistinguished from invasive procedures (including minimally invasiveprocedures) in that the invasive procedures insert a substance or deviceinto or through the skin (or other surface of the body, such as a woundbed) or into an internal body cavity beyond a body orifice.

For example, transcutaneous electrical stimulation of a nerve isnon-invasive because it involves attaching electrodes to the skin, orotherwise stimulating at or beyond the surface of the skin or using aform-fitting conductive garment, without breaking the skin [ThierryKELLER and Andreas Kuhn. Electrodes for transcutaneous (surface)electrical stimulation. Journal of Automatic Control, University ofBelgrade 18(2, 2008):35-45; Mark R. PRAUSNITZ. The effects of electriccurrent applied to skin: A review for transdermal drug delivery.Advanced Drug Delivery Reviews 18 (1996) 395-425]. In contrast,percutaneous electrical stimulation of a nerve is minimally invasivebecause it involves the introduction of an electrode under the skin, vianeedle-puncture of the skin.

Another form of non-invasive electrical stimulation is magneticstimulation. It involves the induction, by a time-varying magneticfield, of electrical fields and current within tissue, in accordancewith Faraday's law of induction. Magnetic stimulation is non-invasivebecause the magnetic field is produced by passing a time-varying currentthrough a coil positioned outside the body. An electric field is inducedat a distance, causing electric current to flow within electricallyconducting bodily tissue. The electrical circuits for magneticstimulators are generally complex and expensive and use a high currentimpulse generator that may produce discharge currents of 5,000 amps ormore, which is passed through the stimulator coil to produce a magneticpulse. The principles of electrical nerve stimulation using a magneticstimulator, along with descriptions of medical applications of magneticstimulation, are reviewed in: Chris HOVEY and Reza Jalinous, The Guideto Magnetic Stimulation, The Magstim Company Ltd, Spring Gardens,Whitland, Carmarthenshire, SA34 0HR, United Kingdom, 2006. In contrast,the magnetic stimulators that are disclosed here are relatively simplerdevices that use considerably smaller currents within the stimulatorcoils. Accordingly, they are intended to satisfy the need forsimple-to-use and less expensive non-invasive magnetic stimulationdevices, for use in treating autism and other developmental conditions,as well as use in treating other conditions.

Potential advantages of such non-invasive medical methods and devicesrelative to comparable invasive procedures are as follows. The patientmay be more psychologically prepared to experience a procedure that isnon-invasive and may therefore be more cooperative, resulting in abetter outcome. Non-invasive procedures may avoid damage of biologicaltissues, such as that due to bleeding, infection, skin or internal organinjury, blood vessel injury, and vein or lung blood clotting.Non-invasive procedures are generally painless and may be performedwithout the dangers and costs of surgery. They are ordinarily performedeven without the need for local anesthesia. Less training may berequired for use of non-invasive procedures by medical professionals. Inview of the reduced risk ordinarily associated with non-invasiveprocedures, some such procedures may be suitable for use by the patientor family members at home or by first-responders at home or at aworkplace. Furthermore, the cost of non-invasive procedures may besignificantly reduced relative to comparable invasive procedures.

In the present invention, noninvasive electrical and/or magneticstimulation of a vagus nerve is used to treat or manage pervasivedevelopmental disorders, such as autism, which are neuro-developmentaldisorders characterized by problems involving a child's socialization,communication, and repetitive or other unusual behavior. Such disordersare listed in entry F84 in the International Statistical Classificationof Diseases and Related Health Problems, 10th Revision (ICD-10). Theyinclude childhood autism (F84.0), atypical autism (F84.1), Rett syndrome(F84.2), other childhood disintegrative disorder (F84.3), overactivedisorder associated with mental retardation and stereotyped movements(F84.4), Asperger syndrome (F84.5), other pervasive developmentaldisorders (F84.8), and unspecified pervasive developmental disorder(F84.9) [World Health Organization. International StatisticalClassification of Diseases and Related Health Problems 10th Revision(ICD-10) Geneva, Switzerland: The WHO (English edition: 10th revision,2008), entry F84].

A similar classification of pervasive developmental disorders appears inThe Diagnostic and Statistical Manual of Mental Disorders, 4th edition(DSM-IV)—Autistic Disorder (299.00), Pervasive Developmental Disorder,Not Otherwise Specified (299.80), Asperger's Disorder (299.80), Rett'sDisorder (299.80), and Childhood Disintegrative Disorder (299.10)[American Psychiatric Association. Criteria for Autism in: Diagnosticand Statistical Manual of Mental disorders (4th ed., text rev.; DSM-IV).Washington, D.C.: The Association (2000), code 299]. However, the 5thedition of The Diagnostic and Statistical Manual of Mental Disorders(DSM-V), which will be forthcoming in 2013, will combine several ofthese disorders (including Asperger syndrome and Pervasive DevelopmentalDisorder Not Otherwise Specified—abbreviated as PDD-NOS) into a singleentity, namely, autism spectrum disorders (ASD).

According to the proposed DSM-V revised criteria for autism spectrumdisorders, an autistic spectrum individual must meet the following A, B,C and D criteria. (A). Persistent deficits in social communication andsocial interaction across contexts, not accounted by generaldevelopmental delays and manifest by all three of the following: (1)Deficits in social-emotional reciprocity . . . ; (2) Deficits innonverbal communicative behaviors used for social interaction . . . ;(3) Deficits in developing and maintaining relationships appropriate todevelopmental level, beyond those with caregivers. (B). Restricted,repetitive patterns of behavior, interests or activities as manifestedby at least two of the following. (1) Stereotyped or repetitive speech,motor movements, or use of objects . . . ; (2) Excessive adherence toroutines, ritualized patterns of verbal or nonverbal behavior, orexcessive resistance to change . . . ; (3) Highly restricted, fixatedinterests that are abnormal in intensity or focus . . . ; (4) Hyper- orhypo-reactivity to sensory input or unusual interests in sensory aspectsof environment . . . ; (C). Symptoms must be present in early childhood. . . ; (D). Symptoms together limit and impair everyday functioning.

Although ASD is already in widespread use as a term, thereconceptualization of ASD in DSM-V is controversial for at least thefollowing reason. Currently, the most common diagnosis among autisticspectrum individuals is PDD-NOS, which is sometimes referred to asatypical “mild autism”. Similarly, Asperger syndrome is sometimesreferred to as a “higher functioning autism”. Some individuals who arepresently diagnosed with Asperger syndrome, as well as PDD-NOSindividuals without repetitive or ritualized behaviors, may not beconsidered autistic under the revised DSM-V criteria. This may affectthe availability of services in the United States that they currentlyobtain (e.g., special schooling, health care, and behavioral therapies).[HAPPE, F. Criteria, categories, and continua: Autism and relateddisorders in DSM-5. Journal of the American Academy of Child &Adolescent Psychiatry 50(2011): 540-542; McPARTLAND, J. C., Reichow, B.,and Volkmar, F. R. Sensitivity and specificity of proposed DSM-5diagnostic criteria for autism spectrum disorder. Journal of theAmerican Academy of Child & Adolescent Psychiatry 51(2012):368-383;WORLEY, A. and Matson, J. L. Comparing symptoms of autism spectrumdisorders using the current DSM-IV-TR diagnostic criteria and theproposed DSM-V diagnostic criteria. Research in Autism SpectrumDisorders 6(2012):965-970; FRAZIER, T. W., Youngstrom, E. A., Speer, L.,Embacher, R., Law, P., Constantino, J. . . . Eng, C. Validation ofproposed DSM-5 criteria for autism spectrum disorder. Journal of theAmerican Academy of Child and Adolescent Psychiatry 51(2012):28-40].

The diagnosis of a particular pervasive developmental disorder, such asautism, is made after extended observation and interaction with a child.Best practices include an initial routine developmental surveillance ofthe child, in which a professional looks for certain age-specificdevelopmental milestones. If the surveillance reveals clinical clues ofpossible autism, it is followed by the diagnosis and evaluation. Ascreening test for autism in young children, often the Checklist forAutism in Toddlers (CHAT), is then conducted. If the CHAT screeningsuggests possible autism, further assessment is performed. The diagnosisof autism (or other developmental disorder) often does not occur untilthe child reaches the age of 3 or 4 [Pauline A. FILIPEK, Pasquale J.Accardo, Grace T. Baranek, et al. The screening and diagnosis ofautistic spectrum disorders. J Autism Dev Disord. 29(6,1999):439-484;FILIPEK P A, Accardo P J, Ashwal S, et al. Practice parameter: screeningand diagnosis of autism: report of the Quality Standards Subcommittee ofthe American Academy of Neurology and the Child Neurology Society.Neurology 55(4, 2000):468-479; New York State Department of Health(NYSDH). Clinical practice guideline: Quick Reference Guide for Parentsand Professionals. Autism/Pervasive developmental disorders assessmentand intervention for young children (age 0-3 years). Publication No.4216, Albany, N.Y. 1999, pp. 1-97; BAIRD, T Charman, A Cox, SBaron-Cohen, J Swettenham, S Wheelwright, and A Drew. Screening andsurveillance for autism and pervasive developmental disorders. Arch DisChild 84(6, 2001): 468-475; KLIN, A., Saulnier, C. D., Tsatsanis, K. D.,& Volkmar, F. R. (2005) Clinical evaluation in autism spectrumdisorders: Psychological assessment within a transdisciplinaryframework. In F. R. Volkmar, R. Paul, A. Klin, & D. Cohen (Eds.),Handbook of autism and pervasive developmental disorders: 3rd Edition,John Wley & Sons, pp. 772-798; Sara Jane WEBB and Emily J. H. Jones.Early Identification of Autism—Early Characteristics, Onset of Symptoms,and Diagnostic Stability Infants & Young Children 22(2, 2009):100-118].

Several testing instruments are commonly used to assess the likelihoodof autism, including The Autism Behavior Checklist (ABC), AutismDiagnostic Interview-Revised (ADI-R), The Childhood Autism Rating Scale(CARS), The Pre-Linguistic Autism Diagnostic Observation Schedule(PL-ADOS), and The Autism Diagnostic Observation Schedule and itsgeneric version (ADOS-G) [SCHOPLER E, Reichler R J, DeVellis R F, DalyK. Toward objective classification of childhood autism: Childhood AutismRating Scale (CARS). J Autism Dev Disord 10(1,1980):91-103; RELLINI E,Tortolani D, Trillo S, Carbone S, Montecchi F. Childhood Autism RatingScale (CARS) and Autism Behavior Checklist (ABC) correspondence andconflicts with DSM-IV criteria in diagnosis of autism. J Autism DevDisord 34(6, 2004):703-708. LORD C, Rutter M, Goode S, Heemsbergen J,Jordan H, Mawhood L, Schopler E. Autism diagnostic observation schedule:a standardized observation of communicative and social behavior. JAutism Dev Disord 19(2,1989):185-212; LORD C, Rutter M, Le Couteur A.Autism Diagnostic Interview-Revised: a revised version of a diagnosticinterview for caregivers of individuals with possible pervasivedevelopmental disorders. J Autism Dev Disord 24(5,1994):659-685;DILAVORE P C, Lord C, Rutter M. The pre-linguistic autism diagnosticobservation schedule. J Autism Dev Disord 25(4,1995):355-379; LORD C,Risi S, Lambrecht L, Cook E H Jr, Leventhal B L, DiLavore P C, PicklesA, Rutter M. The autism diagnostic observation schedule-generic: astandard measure of social and communication deficits associated withthe spectrum of autism. J Autism Dev Disord 30(3, 2000):205-223].

An individual might be diagnosed as having Asperger syndrome under theICD-10 criteria, and autism spectrum disorder under the DSM-V criteria,or Asperger syndrome under DSM-IV criteria. In that regard, a diagnosticcomplication is that under the hierarchical rules of DSM-IV, a dualdiagnosis of autism spectrum disorder with attention-deficithyperactivity disorder (ADHD) is not possible, because signs for theADHD must not be due to the course of a pervasive developmentaldisorder. In contrast, under ICD-10, a dual Asperger and ADHD diagnosisis possible, provided that the Asperger syndrome individual alsoexhibits traits of ADHD such as hyperactivity, impulsiveness, shortattention span, and executive function deficits. This illustrates thediagnostic confusion that is inherent in the use of different diseaseclassifications (ICD versus DSM), which is significant because differentdiagnoses may require different treatments [Michael FITZGERALD and AidenCorvin. Diagnosis and differential diagnosis of Asperger syndrome.Advances in Psychiatric Treatment 7(2001): 310-318]. The confusion mightbe avoided if diagnosis could be made on the basis of laboratory testsrather than solely on the basis of behavioral criteria, but biomarkersthat would be useful for that purpose are not yet available [WALSH P,Elsabbagh M, Bolton P, Singh I. In search of biomarkers for autism:scientific, social and ethical challenges. Nat Rev Neurosci 12(10,2011):603-612; VEENSTRA-VanderWeele J, Blakely R D. Networking inautism: leveraging genetic, biomarker and model system findings in thesearch for new treatments. Neuropsychopharmacology 37(1, 2012):196-212;RATAJCZAK H V. Theoretical aspects of autism: biomarkers—a review. JImmunotoxicol 8(1, 2011):80-94; HENDREN R L, Bertoglio K, Ashwood P,Sharp F. Mechanistic biomarkers for autism treatment. Med Hypotheses73(6, 2009): 950-954; SKJELDAL O H, Sponheim E, Ganes T, Jellum E, BakkeS. Childhood autism: the need for physical investigations. Brain Dev20(4,1998):227-233].

Before the 1990s, the prevalence of autism spectrum disorders wasthought to be no more than 5 per 10,000 individuals. Many recentepidemiological studies tend to conclude that prevalence of autisticdisorder falls between 10 and 20 per 10,000. Some reports find that theincidence is 60 per 10,000 or more. Boys are affected with ASDs morefrequently than are girls by a ratio of 4.3:1. The incidence of allpervasive developmental disorders has been estimated to be between 30and116 per 10,000, with a prevalence of 2.5 per 10,000 for Aspergersyndrome and 15 per 10,000 for PDD-NOS. The data do not show significantprevalence differences according to geographic region, ethnic/culturalfactors, or socioeconomic factors. The increasing prevalence is mostlikely due to the broadening concept of autistic spectrum disorder overthe years and to a greater awareness of these disorders amongprofessionals and the public at large. The lifetime per capitaincremental cost of autism has been estimated to be $3.2 million, withadult care and lost productivity being the largest components of costs[ELSABBAGH M, Divan G, Koh Y J, et al. Global prevalence of autism andother pervasive developmental disorders. Autism Res 5(3, 2012):160-179;NEWSCHAFFER C J, Croen L A, Daniels J, et al. The epidemiology of autismspectrum disorders. Annu Rev Public Health 28(2007):235-258; RUTTER M.Incidence of autism spectrum disorders: changes over time and theirmeaning. Acta Paediatr 94(1, 2005):2-15; GANZ M L. The lifetimedistribution of the incremental societal costs of autism. Arch PediatrAdolesc Med 161(4, 2007):343-349].

Many environmental risk factors have been investigated as potentialcauses of ASD, including certain foods, infectious disease, heavymetals, solvents, diesel exhaust, PCBs, phthalates and phenols used inplastic products, pesticides, brominated flame retardants, alcohol,smoking, illicit drugs, vaccines, and prenatal stress. However, only afew such as rubella exposure have been shown to be significant causativeagents [NEWSCHAFFER C J, Croen L A, Daniels J, et al. The epidemiologyof autism spectrum disorders. Annu Rev Public Health 28(2007):235-258].

Autism has a strong genetic basis, as evidenced by the study of twinsand other relatives of individuals with ASD. However, the genetics ofautism is complex. The number of gene mutations found to carry risk forASD is now well into the hundreds, with no single locus accounting formore than 1% of cases. Furthermore, these mutations may be associatednot only with ASD, but also with disorders such as epilepsy, mentalretardation, and schizophrenia. Some such mutations are particularlyassociated with genetic disorders in which autism is common, such asJoubert Syndrome, Smith-Lemli-Opitz syndrome, Tuberous Sclerosis andFragile X. Practical use of these genetic markers may have to wait untilit is better understood how expression of the genes occurs at differenttimes during the embryological development of the brain [FREITAG C M.The genetics of autistic disorders and its clinical relevance: a reviewof the literature. Mol Psychiatry 12(1, 2007):2-22; KUMAR R A, ChristianS L. Genetics of autism spectrum disorders. Curr Neurol Neurosci Rep9(3, 2009):188-197; GESCHWIND D H. Genetics of autism spectrumdisorders. Trends Cogn Sci 15(9, 2011):409-416; STATE M W, Šestan N.Neuroscience. The emerging biology of autism spectrum disorders. Science337(6100, 2012):1301-1303].

In addition to the above-mentioned genetic syndromes, such as Fragile Xand tuberous sclerosis, autism is frequently comorbid with mooddisorders, phobias, obsessive compulsive disorders, anxiety disorders,and psychosis. As noted above, it is also frequently comorbid withattention deficit hyperactivity disorder, provided that ICD-10 criteriaare used [MATSON J L, Nebel-Schwalm M S. Comorbid psychopathology withautism spectrum disorder in children: an overview. Res Dev Disabil 28(4,2007):341-352]. Intellectual disability or mental handicap (previouslyknown as mental retardation) may occur in as many as 75% of autisticchildren, although special testing methods may be necessary todistinguish autism from intellectual disability [OSTERLING J A, DawsonG, Munson J A. Early recognition of 1-year-old infants with autismspectrum disorder versus mental retardation. Dev Psychopathol 14(2,2002):239-251]. Many other medical symptoms or disorders are commonlyreported in children with autism, including epilepsy, immune systemdysregulation, gastrointestinal symptoms, motor impairment, sensorydysfunction, feeding difficulties/eating disorders, and sleep disorders[NEWSCHAFFER C J, Croen L A, Daniels J, et al. The epidemiology ofautism spectrum disorders. Annu Rev Public Health 28(2007):235-258;TUCHMAN R, Cuccaro M, Alessandri M. Autism and epilepsy: historicalperspective. Brain Dev 32(2010):709-718; TUCHMAN R, Rapin I. Epilepsy inautism. Lancet Neurol 1(6, 2002):352-358; BOLTON P F, Carcani-RathwellI, Hutton J, Goode S, Howlin P, Rutter M. Epilepsy in autism: featuresand correlates. Br J Psychiatry 198(4, 2011):289-294; STAFSTROM C E,Hagerman P J, Pessah I N. Pathophysiology of Epilepsy in Autism SpectrumDisorders. In: Noebels J L, Avoli M, Rogawski M A, Olsen R W,Delgado-Escueta A V, editors. Jasper's Basic Mechanisms of theEpilepsies. 4th edition. Bethesda (Md.): National Center forBiotechnology Information (US), 2012, pp. 1-19; PARDO C A, Vargas D L,Zimmerman A W. Immunity, neuroglia and neuroinflammation in autism. IntRev Psychiatry 17(6, 2005):485-495; ERICKSON C A, Stigler K A, Corkins MR, Posey D J, Fitzgerald J F, McDougle C J. Gastrointestinal factors inautistic disorder: a critical review. J Autism Dev Disord 35(6,2005):713-727; MING X, Brimacombe M, Wagner G C. Prevalence of motorimpairment in autism spectrum disorders. Brain Dev 29(9, 2007):565-570;ROGERS S J, Ozonoff S. Annotation: what do we know about sensorydysfunction in autism? A critical review of the empirical evidence. JChild Psychol Psychiatry 46(12, 2005):1255-1268].

In the remainder of this background section, current methods fortreating or managing pervasive developmental disorders, such as autism,are described. Methods that have been used to treat autism and relateddevelopmental disorders were reviewed extensively and recently in theComparative Effectiveness Review No. 26 of the Agency for HealthcareResearch and Quality of the U.S. Department of Health and HumanServices. That review also analyzes the efficacy of the treatmentmethods [WARREN Z, Veenstra-VanderWeele J, Stone W, et al. Therapies forChildren With Autism Spectrum Disorders. Comparative EffectivenessReview No. 26. (Prepared by the Vanderbilt Evidence-based PracticeCenter under Contract No. 290-2007-10065-I.) AHRQ Publication No.11-EHCO29-EF. Rockville, Md.: Agency for Healthcare Research andQuality. April 2011, 908 pp]. In that publication, treatment methods areorganized into four groups: Behavioral Interventions, EducationalInterventions, Medical Interventions (including dietary methods), AlliedHealth Interventions (e.g., language, sensory, and auditoryinterventions), and Complementary and Alternative Medicine (CAM)Interventions.

Behavioral interventions were the first to show that it is in factpossible to treat autistic children. The interventions may take place athome, at school, and/or at a clinic and may involve a trainedprofessional as well as the parents of the autistic child, often forseveral years of 40 hours per week of one-on-one sessions. Many suchprograms make use of applied behavior analysis in which there is (1) arequest for the child to perform an action, (2) a response on the partof the child, and (3) a consequence which can range from strong positivereinforcement to strong negative reinforcement. As ordinarily practicednowadays, only positive reinforcement is given (typically, verbalpraise, a favored snack food, or time with a preferred toy). The designof the program includes selecting the behaviors or skills that are to beachieved. Thus, the child may be taught social, motor, and verbalbehavior and cognitive skills, and can also be taught not to engage inundesirable behaviors. The program is preferably individualized to theneeds of each child. Individual requests to the child are selected afterhaving first dissected an overall behavior that is desired intocomponent parts, and the training may consist of reinforcing theindividual components, then reinforcing the chain of components so as toachieve the desired overall behavior.

An intervention program will also design the way that reinforcement isapplied at different stages of conditioning the child (e.g., eventuallyeliminating reinforcement after the child has fully acquired the desiredbehavior). Skills may also be exercised in a more natural setting thanthe controlled home or clinical environment in which it was firsttaught. The UCLA/Lovaas-based interventions are perhaps the best knownsuch interventions, but other behavioral intervention programs includespecial social skills interventions, play/interaction-basedinterventions, the Early Start Denver Model (ESDM), less intensiveinterventions focusing on providing parent training, cognitivebehavioral therapy, neurofeedback, and sleep interventions. Whateverintervention method is used, it is advised to begin therapy at as earlyan age as practical, possibly age 2 or 3 [ROGERS S J, Vismara L A.Evidence-based comprehensive treatments for early autism. J Clin ChildAdolesc Psychol 37(1, 2008):8-38; VISMARA L A, Rogers S J. Behavioraltreatments in autism spectrum disorder: what do we know? Annu Rev ClinPsychol 6(2010):447-468]

Educational interventions are also often based on applied behavioranalysis and are sometimes intended for special-needs instruction inelementary schools. Ten such educational programs are reviewed in apublication of the National Research Council. Those programs are asfollows: Children's Unit, Denver Community Based Approach, DevelopmentalIntervention Model, Douglass, Individualized Support Program, LEAP,Pivotal response training, TEACCH, UCLA Young Autism Project, and Walden[Catherine LORD and James P. McGee, Eds., and National Research CouncilCommittee on Educational Interventions for Children with Autism.Educating children with autism. Washington, D.C.: National Academy Press(2001)].

There are a few medical interventions for ASD, but no medications arecurrently available to treat its core symptoms. However, there ispreliminary evidence that the diuretic bumetanide might be helpful[LEMONNIER E, Degrez C, Phelep M, Tyzio R, Josse F, Grandgeorge M,Hadjikhani N, Ben-Ari Y. A randomised controlled trial of bumetanide inthe treatment of autism in children. Transl Psychiatry 2(2012):e202, pp.1-8]. Also, evidence favors the use of medications to addresschallenging behaviors of autistic children, using risperidone andaripiprazole (for tantrums, disruptive behavior, aggression towardsothers, self-injury, quickly changing moods, and irritability) [LESKOVECT J, Rowles B M, Findling R L. Pharmacological treatment options forautism spectrum disorders in children and adolescents. Hary RevPsychiatry 16(2, 2008):97-112; McPHEETERS M L, Warren Z, Sathe N, BruzekJ L, Krishnaswami S, Jerome R N, Veenstra-Vanderweele J. A systematicreview of medical treatments for children with autism spectrumdisorders. Pediatrics 127(5, 2011):e1312-e1321]. Drugs are also used totreat co-morbid conditions of autism, such as epilepsy.

A large number of dietary supplement, special diet, language, sensory,and auditory interventions, as well as complementary and alternativemedicine interventions have been used to treat the symptoms of autism.According to ROSSIGNOL, melatonin, antioxidants, acetylcholinesteraseinhibitors, naltrexone, and music therapy appear to show benefits. LEVYrecommended the use of melatonin but found that there was insufficientevidence to recommend the use of other such therapies [ROSSIGNOL D A.Novel and emerging treatments for autism spectrum disorders: asystematic review. Ann Clin Psychiatry 21(4, 2009):213-236; LEVY S E,Hyman S L. Complementary and alternative medicine treatments forchildren with autism spectrum disorders. Child Adolesc Psychiatr Clin NAm 17(4, 2008):803-820].

When acupuncture is used to treat autistic individuals, the points ofstimulation are LI4 on the hand where the thumb and first finger meet,PC6 on the palm-side of the forearm above the crease of the wrist, ST36on the calf near the knee, and SP6 on the calf near the ankle. Theputative mechanism of such acupuncture treatment is via changes inlevels of arginine-vasopressin and oxytocin [ZHANG R, Jia M X, Zhang JS, Xu X J, Shou X J, Zhang X T, Li L, Li N, Han S P, Han J S.Transcutaneous electrical acupoint stimulation in children with autismand its impact on plasma levels of arginine-vasopressin and oxytocin: aprospective single-blinded controlled study. Res Dev Disabil 33(4,2012):1136-1146]. Apparently, no acupuncture point in the vicinity of avagus nerve is used.

Magnetic stimulation has been used in an attempt to treat, diagnose, orcharacterize potentially autistic individuals. However, those magneticstimulation methods, transcranial magnetic stimulation and transcranialdirect current stimulation, have been applied only to the brain of thoseindividuals, and not to a peripheral nerve, as disclosed here[DEMIRTAS-Tatlidede A, Vahabzadeh-Hagh A M, Pascual-Leone A. Cannoninvasive brain stimulation enhance cognition in neuropsychiatricdisorders? Neuropharmacology 64(2013):566-578; Xuejun KONG. Clinicalsignificance of functional MRI guided transcranial magnetic stimulationfor autism. N A J Med Sci. 2(2, 2009):64-66; OBERMAN L, Eldaief M,Fecteau S, Ifert-Miller F, Tormos J M, Pascual-Leone A. Abnormalmodulation of corticospinal excitability in adults with Asperger'ssyndrome. Eur J Neurosci 36(6, 2012):2782-2788; SOKHADZE E, Baruth J,Tasman A, Mansoor M, Ramaswamy R, Sears L, Mathai G, El-Baz A, CasanovaM F. Low-frequency repetitive transcranial magnetic stimulation (rTMS)affects event-related potential measures of novelty processing inautism. Appl Psychophysiol Biofeedback 35(2, 2010):147-161; SOKHADZE EM, El-Baz A, Baruth J, Mathai G, Sears L, Casanova M F. Effects of lowfrequency repetitive transcranial magnetic stimulation (rTMS) on gammafrequency oscillations and event-related potentials during processing ofillusory figures in autism. J Autism Dev Disord 39(4, 2009):619-634;STAMOULIS C, Oberman L M, Praeg E, Bashir S, Pascual-Leone A. Singlepulse TMS-induced modulations of resting brain neurodynamics encoded inEEG phase. Brain Topogr 24(2, 2011):105-113].

Invasive vagus nerve stimulation (VNS) is currently approved for thetreatment of epilepsy in children older than 12 years, includingchildren with autism spectrum disorders (also including Aspergersyndrome children) and other pervasive developmental disorders such asRett's syndrome. VNS may also be used investigationally in youngerchildren as well, also including children with autism spectrum disorders[James W. WHELESS. Vagus nerve stimulation in pediatrics: determiningappropriate candidates. Advanced Studies in Medicine 5(5B, 2005):S474-S476; BLOUNT J P, Tubbs R S, Kankirawatana P, Kiel S, Knowlton R,Grabb P A, Bebin M Vagus nerve stimulation in children less than 5 yearsold. Child's Nervous System 22(9, 2006):1167-1169]. Approximately 30% ofepileptic children also have autism spectrum disorders, andapproximately 30% of individuals with autism spectrum disorders haveepilepsy [TUCHMAN R, Cuccaro M, Alessandri M. Autism and epilepsy:historical perspective. Brain Dev 32(2010):709-718; TUCHMAN R, Rapin I.Epilepsy in autism. Lancet Neurol 1(6, 2002):352-358; BOLTON P F,Carcani-Rathwell I, Hutton J, Goode S, Howlin P, Rutter M. Epilepsy inautism: features and correlates. Br J Psychiatry 198(4, 2011):289-294].Consequently, some data exist not only as to whether VNS is useful forthe treatment of epilepsy in autistic children, but also whether the VNSaffects the childrens' austic symptoms. However, the parameters of theelectrical stimulation were chosen to treat the epilepsy, and not theautism, so the data concerning changes of autistic symptoms areessentially accounts of the side effects of the epilepsy treatment.

DANIELSSON et al. used invasive VNS to treat eight autistic children,four of which had also been diagnosed as having attention deficithyperactivity disorder. They reported that two years of VNS treatmentdid not decrease the frequency of epileptic seizures in the children andhad no positive cognitive effects. In one child, negative changes ofgeneral functioning were observed, but in three children, minorimprovements in general functioning were measured through use ofstandard tests (Autistic Behavior Checklist; Autism DiagnosticObservation Schedule, Children's Global Assessment Scale, and ClinicalGlobal Impressions-Improvement scale). The number of children was small,and there was no control group, so it is not clear from these datawhether any changes in austistic symptoms were due to the VNS treatment,to other diverse treatments that the children were also receiving, or tothe natural progression of autistic symptoms [DANIELSSON S, Viggedal G,Gillberg C, Olsson I. Lack of effects of vagus nerve stimulation ondrug-resistant epilepsy in eight pediatric patients with autism spectrumdisorders: a prospective 2-year follow-up study. Epilepsy Behav 12(2,2008):298-304].

MURPHY et al. performed invasive VNS with six patients with medicallyrefractory epilepsy secondary to hypothalamic hamartomas, four of whichhad severe autistic behaviors. Seizure control was found in three of thepatients, and improved behavior was observed in all four of the autisticchildren [MURPHY J V, Wheless J W, Schmoll C M. Left vagal nervestimulation in six patients with hypothalamic hamartomas. Pediatr Neurol23(2, 2000):167-168]. In patent application US20050187590, entitledMethod and system for providing therapy for autism by providingelectrical pulses to the vagus nerve(s), to BOJ EVA et al, thepublication by MURPHY was noted, and it was further disclosed that animplanted vagus nerve stimulator could be used to treat autism. However,unlike the present disclosure, their application did not disclose anystep that is unique to the treatment of autism or to a relatedneuro-developmental disorder.

LEVY et al examined a registry of patients with implanted VNSstimulators and found that after treatment, patients with autism haveepileptic symptoms that are similar to those of patients without autism.Among quality of life indicators only the one, improved mood after 12months of treatment, was found to be better in autistic patients ascompared with non-autistic patients [LEVY M L, Levy K M, Hoff D, Amar AP, Park M S, Conklin J M, Baird L, Apuzzo M L. Vagus nerve stimulationtherapy in patients with autism spectrum disorder and intractableepilepsy: results from the vagus nerve stimulation therapy patientoutcome registry. J Neurosurg Pediatr 5(6, 2010):595-602].

PARK investigated 59 epileptic patients with autism, nineteen of whomhad Lennox-Gastaut syndrome. He found that more than half of thepatients had a reduction in seizure frequency after 12 months and thatthe quality of life generally improved in the patients, with some 76% ofthem experiencing an improved alertness [PARK Y D. The effects of vagusnerve stimulation therapy on patients with intractable seizures andeither Landau-Kleffner syndrome or autism. Epilepsy Behav 4(3,2003):286-290].

WARWICK et al described the case of one epileptic patient with Aspergersyndrome. After six months of treatment using invasive VNS, the numberof seizures and the duration of seizures were reduced. Furthermore,using modified Yale-Brown Obsessive Compulsive Scale and quality of lifescales, after six months of VNS treatment, the patient was found to haveimproved Abnormal Nonverbal, Social Interaction, and Emotional Scores,as well as improved mood and memory [WARWICK T C, Griffith J, Reyes B,Legesse B, Evans M. Effects of vagus nerve stimulation in a patient withtemporal lobe epilepsy and Asperger syndrome: case report and review ofthe literature. Epilepsy Behav 10(2, 2007):344-347].

WILFONG described the use of VNS treatment for epilepsy in seven Rettsyndrome patients. The investigators found that after 12 months oftreatment, there was a decrease in seizure frequency in six of them,that the patients were more alert, but there were not changes in mood orcommunication abilities [WILFONG A A, Schultz R J. Vagus nervestimulation for treatment of epilepsy in Rett syndrome. Dev Med ChildNeurol 48(8, 2006):683-686].

The publications that were cited above suggest that invasive vagus nervestimulation may be useful in the treatment of autistic children who haveepilepsy. WALKER et al performed animal experiments that addressed theissue of whether there are common neural pathways relating to seizuresand autism-like behaviors, which may explain why epilepsy is found inapproximately 30% of autistic children. They made lesions in rats thatspecifically target forebrain and cerebellar neurons, in order to createbehaviors in rats that are similar to behavioral deficits seen inepilepsy and autism. They conclude that epilepsy and autism may havecommon neural pathways, and when that is the case, VNS might be used asa treatment for the autism [WALKER B R, Diefenbach K S, Parikh T N.Inhibition within the nucleus tractus solitarius (NTS) amelioratesenvironmental exploration deficits due to cerebellum lesions in ananimal model for autism. Behav Brain Res 176(1, 2007):109-120].

However, there is no suggestion in these publications that vagus nervestimulation could be used to treat autistic children who do not haveepilepsy, and in fact, the parameters of the nerve stimulation (pulsewidth, frequency, etc.) were chosen to treat the epilepsy, withoutregard to the symptoms of autism. Furthermore, there is no suggestionthat the vagus nerve stimulation could be applied noninvasively.Similarly, the use of deep brain stimulation to treat autism has onlybeen mentioned in connection with the primary treatment of anotherdisorder such as epilepsy or movement disorders [Anya McLAREN. Deepbrain stimulation: a potential therapy for epilepsy and movementdisturbances in autism spectrum disorders? Journal on DevelopmentalDisabilities 13 (3, 2007): 167-186]. However, something similar to deepbrain stimulation for the treatment of autism was disclosed in U.S. Pat.No. 7,623,927, entitled Modulation of the brain to affect psychiatricdisorders, to REZAI, and in application US20090326605, entitledTreatment of language, behavior and social disorders, to MORRELL.

The psychology literature also refers to vagus nerve stimulation inyoung children who are at risk for developmental difficulties, but thatstimulation consists of massage, kangaroo care, and similar tactileinterventions, not electrical stimulation of the vagus nerve. Therationale for such tactile intervention is that the vagus nerve in theat-risk children has low tone, as evidenced primarily by unusually lowrespiratory sinus arrhythmia. The tactile stimulation is thought toincrease the vagal tone, resulting in more normal attentiveness, facialexpressions and vocalizations [FIELD T, Diego M. Vagal activity, earlygrowth and emotional development. Infant Behav Dev 31(3, 2008):361-373].

PORGES and colleagues expand on that concept, arguing that developmentaldisorders are caused by, or are associated with, abnormalities in theautonomic nervous system generally, because the autonomic nervous systemmodulates affective experience, emotional expression, facial gestures,vocal communication and contingent social behavior. As an example,PORGES points to rocking and swinging of an autistic child, in which theposition of the head is changed relative to the position of the heart.This will stimulate the baroreceptors and thereby engage autonomicheartrate/blood pressure feedback control loops. According to PORGES,this suggests that the frequently observed rocking and swingingbehaviors in autistic individuals may reflect a naturally occurringbiobehavioral strategy to stimulate and regulate a vagal system that isnot efficiently functioning. However, despite his recognition of thepotential of vagus nerve stimulation to help epileptic individuals withautistic-like behavior as described above in the publication by MURPHY,PORGES did not develop vagus nerve stimulation interventions to treatautonomic dysfunction in autistic children. Instead, he disclosed abehavioral intervention that uses acoustic stimulation to improve socialbehavior, and tested the approach with children diagnosed with autism.With that intervention, computer altered acoustic stimulation waspresented in 45-min sessions, during which attempts were made tomaintain the child in a calm behavioral state [PORGES S W. The polyvagaltheory: phylogenetic substrates of a social nervous system. Int JPsychophysiol 42(2, 2001):123-46; PORGES S W. The Polyvagal Theory:phylogenetic contributions to social behavior. Physiol Behav 79(3,2003):503-513; PORGES S W, Furman S A. The Early Development of theAutonomic Nervous System Provides a Neural Platform for Social Behavior:A Polyvagal Perspective. Infant Child Dev 20(1, 2011):106-118].

In the present disclosure, applicants teach the use of noninvasive vagusnerve stimulation (VNS) to treat autism spectrum disorders and otherpervasive developmental disorders, irrespective of whether the patientalso experiences epileptic seizures. One problem that may arise inperforming the VNS noninvasively is that it requires the cooperation ofthe patient when applying the stimulator for an extended period of timeto the patient's neck. For children with behavioral problems, theinvention teaches that restraining the problematic child to apply thestimulator may not be necessary, provided that the child is initiallytaught or trained to actually want the stimulator to be applied. Thus,in one aspect of the invention, the child is initially stimulatednoninvasively in such a way as to feel euphoric and therefore will notresist subsequent applications of the stimulator. Methods for creating aeuphoric mental state using VNS were disclosed in a commonly assigned,co-pending application Ser. No. 13/024,727, entitled Non-invasivemethods and devices for inducing euphoria in a patient and theirtherapeutic application, to SIMON et al, which is hereby incorporated byreference.

Having achieved the willingness of the child to undergo the noninvasiveVNS through the induction of euphoria, the euphoric stimulation mightthen be provided only when the child performs a desirable task, therebyusing the VNS as a conditioning stimulus for behavioral therapy. Inanother aspect of the invention, disclosed waveforms of the VNS areselected to inhibit or activate particular neural networks of the brainthat are associated with autistic behavior and that become abnormalduring the course of a child's development. That is to say, theinvention is intended to provide a much-needed medical intervention. Themethods may also be applicable to psychological developmental disordersgenerally. Such disorders include disorders of psychological developmentother than pervasive developmental disorders (i.e., ICD 10classifications F80-F89 other than F84) and Intellectual DevelopmentalDisorders (i.e. ICD 10 classifications F70-F79) which, like autism, havea strong genetic basis for causing developmental cognitive abnormalities(e.g., Down syndrome, Klinefelter's syndrome, Fragile X syndrome,neurofibromatosis, congenital hypothyroidism, Williams syndrome,phenylketonuria and Prader-Willi syndrome). The methods may also beapplicable to some behavioral and emotional disorders with onset usuallyoccurring in childhood and adolescence (ICD 10 classifications F90-F98),which are commonly comorbid with autism. This would include disturbancesof activity and attention (attention deficit disorder, F90.0).

SUMMARY OF THE INVENTION

The present invention involves devices and methods for the treatment orprevention of autism and other neurodevelomental disorders. The patientmay be a pregnant mother who is at risk for having an autistic child, anindividual who is potentially autistic, or an individual who is actuallydiagnosed as being autistic. For such individuals, the treatment may beas a newborn, an infant, a toddler, a young child, an older child, ayoung adult, or an adult. In certain aspects of the invention, a deviceor system comprises an energy source of magnetic and/or electricalenergy that is transmitted non-invasively to, or in close proximity to,a selected nerve of the patient to temporarily stimulate and/or modulatethe signals in the selected nerve. In preferred embodiments of theinvention, the selected nerve is a vagus nerve in the patient's neck.

In one aspect of the invention, an autistic child is stimulatednoninvasively in such a way as to feel euphoric so that he or she willnot resist subsequent applications of the stimulator. Methods forcreating a euphoric mental state using vagus nerve stimulation weredisclosed in a commonly assigned, co-pending application Ser. No.13/024,727, entitled Non-invasive methods and devices for inducingeuphoria in a patient and their therapeutic application, to SIMON et al.Having achieved the willingness of the child to undergo the noninvasiveVNS through the induction of euphoria, the euphoric stimulation may thenbe provided as a conditioning stimulus for treatment of the autism. Thedisclosure describes treating impairment in the use of non-verbalbehaviors and in improving development of peer relationships. It alsodescribes methods for promoting the sharing of interests with others,increased social reciprocity, the use of spoken or nonverbal language,the non-repetition of words, engagement in conversation, novelty inpretend play, interest in a new subject, flexibility in routines or theloss of ritual behavior, the loss of repetitive or stereotyped behavior,and the loss of preoccupation with particular objects.

In another aspect of the invention, vagus nerve stimulation is performedon a pregnant woman, preferably during the first trimester, in order toprevent abnormal neurodevelopment of the fetus. The interventionmodulates the mother's circulating levels of serotonin by stimulatingenterochromaffin cells in the gut. This intervention is intendedespecially for women who are taking serotonin reuptake inhibitors or whoare using cocaine. It may also be useful for women who may pass on anautism gene variant to her child, the gene variant being one thatresults in an overactive serotonin transporter.

In another aspect of the invention, vagus nerve stimulation of a newbornor infant is used to increase the activity of raphe nuclei to producemore serotonin in the newborn's brain, especially among those newbornswho have demonstrable hyper-serotonemia due to an overactive serotonintransporter.

In another aspect of the invention, vagus nerve stimulation is used as aprophylaxis or countermeasure against unusual patterns of a child'sgrowth, especially during the first and second years, through modulationof the activity of growth factors, comprising BDNF, FGF-2, FGF-7,FGF-22, HGF/SF, IGF-1, VEGF, and serotonin.

In another aspect of the invention, vagus nerve stimulation is used topromote neuronal excitation-inhibition balance, particularly byincreasing the number of inhibitory GABAergic synapses throughout thedeveloping brain of a newborn or young child who is at risk for becomingautistic. The parameters of the vagus nerve stimulation may be selectedor adjusted in such a way as to prevent or reduce abnormal highfrequency components in the EEG of the child, which is a measure ofexcitation-inhibition imbalance.

For children and adults who are autistic, vagus nerve stimulation mayalso be used to promote neuronal excitation-inhibition balance, byacting in opposition to glutamate-mediated excitation of nerve tissue,through the inhibitory effects of GABA, and/or serotonin, and/ornorepinephrine that are released from the periaqueductal gray, raphenucei, and locus coeruleus, respectively.

The brain contains several neural networks that can be identified bybrain imaging, which are known as resting state networks. Examples ofsuch networks include the default mode network (DMN), the ventralattention network (VAN), and networks that include the anterior insula(AI) and anterior cingulate cortex (ACC). The locus ceruleus is thoughtto project to all of the resting state networks. Vagus stimulationmethods of the present invention increase norepinephrine levels in aresting state network, wherein a particular resting state network may bepreferentially stimulated via the locus ceruleus, by using a vagus nervestimulation waveform that entrains to the signature EEG pattern of thatnetwork. Depending on the distribution of adrenergic receptor subtypeswithin the resting state network, the vagus nerve stimulation maydeactivate or activate the network. Deactivation of a resting statenetwork may also be accomplished by activating another resting statenetwork, which causes deactivation of other networks.

Resting state networks may be abnormal in individuals with autism, whichmay be identified using fMRI measurement. The measurements may point toabnormalities in particular networks such as the default mode networkand networks related attention, salience, and the processing of sensoryinformation. They may also point to abnormalities in the switching ortoggling between networks. The present invention modulates the activitysuch resting state networks via the locus ceruleus, by training anabnormal resting state network to become more normal. For example, thetraining increases the activity of a resting state network that isabnormally inactive. It may also attempt to change the signature EEGpattern of a network, by slowly changing the frequency content of thestimulation & EEG pattern of the network to which the stimulator isentrained. The training may be accompanied by other modalities ofsensory stimulation, such as sound, successive pictures of faces, etc.

For some patients, the stimulation may be performed for 30 minutes, andthe treatment is initially performed several times a week for 12 weeksor longer to observe its effect on behavior, EEG, respiratory sinusarrhythmia, or other biomarkers. If the patient is a pregnant woman, thetreatment is preferably performed during the first trimester. Forchildren or adults who are potentially or actually autistic, thetreatment may in some cases be essentially continuous. For patientsexperiencing intermittent behavioral symptoms, the treatment may beperformed only when the patient is symptomatic. However, it isunderstood that parameters of the stimulation protocol may be varied inresponse to heterogeneity in the symptoms of patients. Differentstimulation parameters may also be selected as the course of thepatient's neurodeveloment changes. In preferred embodiments, thedisclosed methods and devices do not produce clinically significant sideeffects, such as agitation or anxiety, or changes in heart rate or bloodpressure. It is understood that the stimulation may also make use of animplanted vagus nerve stimulator, particularly in children who areotherwise being treated for epilepsy (but generally using stimulationparameters to treat the autism rather than the epilepsy), or innon-epileptic children who cannot adapt to the use of a noninvasivestimulator.

In one embodiment, the method of treatment includes positioning the coilof a magnetic stimulator non-invasively on or above a patient's neck andapplying a magnetically-induced electrical impulse non-invasively to thetarget region within the neck to stimulate or otherwise modulateselected nerve fibers. In another embodiment, surface electrodes areused to apply electrical impulses non-invasively to the target regionwithin the neck to likewise stimulate or otherwise modulate selectednerve fibers. Preferably, the target region is adjacent to, or in closeproximity with, the carotid sheath that contains a vagus nerve.

The non-invasive magnetic stimulator device is used to modulateelectrical activity of a vagus nerve, without actually introducing amagnetic field into the patient. The preferred stimulator comprises twotoroidal windings that lie side-by-side within separate stimulatorheads, wherein the toroidal windings are separated by electricallyinsulating material. Each toroid is in continuous contact with anelectrically conducting medium that extends from the patient's skin tothe toroid. The currents passing through the coils of the magneticstimulator will saturate its core (e.g., 0.1 to 2 Tesla magnetic fieldstrength for Supermendur core material). This will require approximately0.5 to 20 amperes of current being passed through each coil, typically 2amperes, with voltages across each coil of 10 to100 volts. The currentis passed through the coils in bursts of pulses, as described below,shaping an elongated electrical field of effect.

In another embodiment of the invention, the stimulator comprises asource of electrical power and two or more remote electrodes that areconfigured to stimulate a deep nerve. The stimulator may comprise twoelectrodes that lie side-by-side within a hand-held enclosure, whereinthe electrodes are separated by electrically insulating material. Eachelectrode is in continuous contact with an electrically conductingmedium that extends from the interface element of the stimulator to theelectrode. The interface element also contacts the patient's skin whenthe device is in operation.

Current passing through an electrode may be about 0 to 40 mA, withvoltage across the electrodes of about 0 to 30 volts. The current ispassed through the electrodes in bursts of pulses. There may be 1 to 20pulses per burst, preferably five pulses. Each pulse within a burst hasa duration of about 20 to 1000 microseconds, preferably 200microseconds. A burst followed by a silent inter-burst interval repeatsat 1 to 5000 bursts per second (bps, similar to Hz), preferably at 15-50bps, and even more preferably at 25 bps. The preferred shape of eachpulse is a full sinusoidal wave.

A source of power supplies a pulse of electric charge to the electrodesor magnetic stimulator coil, such that the electrodes or magneticstimulator produce an electric current and/or an electric field withinthe patient. The electrical or magnetic stimulator is configured toinduce a peak pulse voltage sufficient to produce an electric field inthe vicinity of a nerve such as a vagus nerve, to cause the nerve todepolarize and reach a threshold for action potential propagation. Byway of example, the threshold electric field for stimulation of thenerve may be about 8 V/m at 1000 Hz. For example, the device may producean electric field within the patient of about 10 to 600 V/m (preferablyless than 100 V/m) and an electrical field gradient of greater than 2V/m/mm. Electric fields that are produced at the vagus nerve aregenerally sufficient to excite all myelinated A and B fibers, but notnecessarily the unmyelinated C fibers. However, by using a reducedamplitude of stimulation, excitation of A-delta and B fibers may also beavoided.

The preferred stimulator shapes an elongated electric field of effectthat can be oriented parallel to a long nerve, such as a vagus. Byselecting a suitable waveform to stimulate the nerve, along withsuitable parameters such as current, voltage, pulse width, pulses perburst, inter-burst interval, etc., the stimulator produces acorrespondingly selective physiological response in an individualpatient. Such a suitable waveform and parameters are simultaneouslyselected to avoid substantially stimulating nerves and tissue other thanthe target nerve, particularly avoiding the stimulation of nerves in theskin that produce pain.

Treating or averting autism or other neurodevelopmental disorders may beimplemented within the context of control theory. A controllercomprising, for example, one of the disclosed vagus nerve stimulators, aPID, and a feedforward model, provides input to the patient viastimulation of one or both of the patient's vagus nerves. In oneembodiment, the vagus nerve stimulation is varied as a function of thephase of respiration, in order to train the patient's autonomic nervoussystem so as to increase his abnormally low respirator sinus arrhythmia.Feedforward models may be black box models, particularly models thatmake use of support vector machines. Data for training and exercisingthe models are from noninvasive physiological and/or environmentalsignals obtained from sensors located on or about the patient. Adisclosed model predicts the imminent onset of motor stereotypies (e.g.,hand flapping, or rocking and swinging), which may be averted throughuse of vagus nerve stimulation. If the symptoms are in progress, thevagus nerve stimulation may be used to terminate them.

The novel systems, devices and methods for treating autism and otherneuro-developmental disorders are more completely described in thefollowing detailed description of the invention, with reference to thedrawings provided herewith, and in claims appended hereto. Otheraspects, features, advantages, etc. will become apparent to one skilledin the art when the description of the invention herein is taken inconjunction with the accompanying drawings.

INCORPORATION BY REFERENCE

Hereby, all issued patents, published patent applications, andnon-patent publications that are mentioned in this specification areherein incorporated by reference in their entirety for all purposes, tothe same extent as if each individual issued patent, published patentapplication, or non-patent publication were specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims.

FIG. 1 shows structures within a patient's nervous system that may beabnormal in autistic patients, or within a pregnant woman who is at riskfor having an autistic child, the physiology of which may be modulatedby electrical stimulation of a vagus nerve.

FIG. 2A is a schematic view of an exemplary nerve modulating deviceaccording to the present invention which supplies controlled pulses ofelectrical current to (A) a magnetic stimulator coil.

FIG. 2B is a schematic view of another embodiment of a nerve modulatingdevice according to the present inventin which supplies electricalcurrent to surface electrodes.

FIG. 2C illustrates an exemplary electrical voltage/current profileaccording to the present invention.

FIG. 2D illustrates an exemplary waveform for stimulating and/ormodulating impulses that are applied to a nerve.

FIG. 2E illustrates another exemplary waveform for stimulating and/ormodulating impulses applied to a nerve.

FIG. 3A is a perspective view of the top of a dual-toroid magneticstimulator coil according to an embodiment of the present invention.

FIG. 3B is a perspective view of the bottom of the magnetic stimulatorcoil of FIG. 3A.

FIG. 3C is a cut-a-way view of the magnetic stimulator coil of FIG. 3A.

FIG. 3D is another cut-a-way view of the magnetic stimulator coil ofFIG. 3A.

FIG. 3E illustrates the magnetic stimulator coil of FIGS. 3A-3D attachedvia cable to a box containing the device's impulse generator, controlunit, and power source.

FIG. 4A is a perspective view of a dual-electrode stimulator accordingto another embodiment of the present invention.

FIG. 4B is a cut-a-way view of the dual-electrode stimulator of FIG. 4A.

FIG. 4C is an exploded view of one of the electrode assemblies of thedual-electrode stimulator of FIG. 4A.

FIG. 4D is a cut-a-way view of the electrode assembly of FIG. 4C.

FIG. 5A is perspective view of the top of an alternative embodiment ofthe dual-electrode stimulator of FIG. 4A.

FIG. 5B is a perspective view of the bottom of the dual-electrodestimulator of FIG. 5A.

FIG. 5C is a cut-a-way view of the dual-electrode stimulator of FIG. 5A.

FIG. 5D is another cut-a-way view of the dual-electrode stimulator ofFIG. 5A.

FIG. 6A illustrates the approximate position of the housing of thestimulator according one embodiment of the present invention, when usedto stimulate the right vagus nerve in the neck of an adult patient.

FIG. 6B illustrates the approximate position for stimulation of a child.

FIG. 7 illustrates the housing of the stimulator according oneembodiment of the present invention, when positioned to stimulate avagus nerve in the patient's neck, wherein the stimulator is applied tothe surface of the neck in the vicinity of the identified anatomicalstructures.

FIG. 8 illustrates connections between the controller and controlledsystem according to the present invention, their input and outputsignals, and external signals from the environment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In one embodiment of the invention, a time-varying magnetic field,originating and confined to the outside of a patient, generates anelectromagnetic field and/or induces eddy currents within tissue of thepatient. In another embodiment, electrodes applied to the skin of thepatient generate currents within the tissue of the patient. An objectiveof the invention is to produce and apply the electrical impulses so asto interact with the signals of one or more nerves, in order to achievethe therapeutic result of altering a disorder of psychologicaldevelopment, more particularly a pervasive developmental disorder, andeven more particularly, the disorder of autism. In the disclosure thatfollows, the developmental condition is usually referred to as autism,but with the understanding that unless otherwise indicated, thediscussion could apply to other conditions of psychological developmentas well [Geraldine DAWSON and Karen Toth. Autism spectrum disorders.Chapter 8 (pp. 317-357) In: Developmental Psychopathology. Vol 3. Risk,Disorder, and Adaptation, 2nd Edn., Dante Cicchetti and Donald J Cohen,eds. Hoboken: N.J.: John Wiley & Sons: (2006); LEVY S E, Mandell D S,Schultz R T. Autism. Lancet 374(9701, 2009):1627-1638; William JBARBARESI. Autism: a review of the state of the science for pediatricprimary health care clinicians. Arch Pediatr Adolesc Med160(2006):1167-1175; RAPIN I, Tuchman R F. Autism: definition,neurobiology, screening, diagnosis. Pediatr Clin North Am 55(5,2008):1129-1146; VOLKMAR F R, Lord C, Bailey A, Schultz R T, Klin A.Autism and pervasive developmental disorders. J Child Psychol Psychiatry45(1, 2004):135-170; Ami KLIN. Autism and Asperger syndrome: anoverview. Rev Bras Psiquiatr 28(Supl I, 2006):53-S11].

Much of the disclosure will be directed specifically to treatment of apatient by electromagnetic stimulation in or around a vagus nerve, withdevices positioned non-invasively on or near a patient's neck. However,it will also be appreciated that the devices and methods of the presentinvention can be applied to other tissues and nerves of the body,including but not limited to other parasympathetic nerves, sympatheticnerves, spinal or cranial nerves. As recognized by those having skill inthe art, the methods should be carefully evaluated prior to use inpatients known to have preexisting cardiac issues.

FIG. 1 shows the location of the stimulation as “Vagus NerveStimulation,” relative to its connections with other anatomicalstructures that are affected by the stimulation. In differentembodiments of the invention, various brain and brainstem structures arepreferentially modulated by the stimulation, and in another embodimentof the invention the objective is to stimulate certain cells located inthe gut (enterochromaffin cells). These structures will be described insections of the disclosure that follow, along with the rationale formodulating their activity as a prophylaxis or treatment for autism orother neurodevelopmental disorders. As a preliminary, we first describethe vagus nerve itself and its most proximal connections, which areparticularly relevant to the disclosure below of the electricalwaveforms that are used to perform the stimulation.

The vagus nerve (tenth cranial nerve, paired left and right) is composedof motor and sensory fibers. The vagus nerve leaves the cranium, passesdown the neck within the carotid sheath to the root of the neck, thenpasses to the chest and abdomen, where it contributes to the innervationof the viscera, including the gut that contains enterochromaffin cells.

A vagus nerve in man consists of over 100,000 nerve fibers (axons),mostly organized into groups. The groups are contained within fasciclesof varying sizes, which branch and converge along the nerve. Undernormal physiological conditions, each fiber conducts electrical impulsesonly in one direction, which is defined to be the orthodromic direction,and which is opposite the antidromic direction. However, externalelectrical stimulation of the nerve may produce action potentials thatpropagate in orthodromic and antidromic directions. Besides efferentoutput fibers that convey signals to the various organs in the body fromthe central nervous system, the vagus nerve conveys sensory (afferent)information about the state of the body's organs back to the centralnervous system. Some 80-90% of the nerve fibers in the vagus nerve areafferent (sensory) nerves, communicating the state of the viscera to thecentral nervous system. Propagation of electrical signals in efferentand afferent directions are indicated by arrows in FIG. 1 . Ifcommunication between structures is bidirectional, this is shown in FIG.1 as a single connection with two arrows, rather than showing theefferent and afferent nerve fibers separately.

The largest nerve fibers within a left or right vagus nerve areapproximately 20 μm in diameter and are heavily myelinated, whereas onlythe smallest nerve fibers of less than about 1 μm in diameter arecompletely unmyelinated. When the distal part of a nerve is electricallystimulated, a compound action potential may be recorded by an electrodelocated more proximally. A compound action potential contains severalpeaks or waves of activity that represent the summated response ofmultiple fibers having similar conduction velocities. The waves in acompound action potential represent different types of nerve fibers thatare classified into corresponding functional categories, withapproximate diameters as follows: A-alpha fibers (afferent or efferentfibers, 12-20 μm diameter), A-beta fibers (afferent or efferent fibers,5-12 μm), A-gamma fibers (efferent fibers,3-7 μm), A-delta fibers(afferent fibers, 2-5 μm), B fibers (1-3 μm) and C fibers (unmyelinated,0.4-1.2 μm). The diameters of group A and group B fibers include thethickness of the myelin sheaths. It is understood that the anatomy ofthe vagus nerve is developing in newborns and infants, which accounts inpart for the maturation of autonomic reflexes. Accordingly, it is alsounderstood that the parameters of vagus nerve stimulation in the presentinvention are chosen in such a way as to account for this age-relatedmaturation [PEREYRA P M, Zhang W, Schmidt M, Becker L E. Development ofmyelinated and unmyelinated fibers of human vagus nerve during the firstyear of life. J Neurol Sci 110(1-2, 1992):107-113; SCHECHTMAN V L,Harper R M, Kluge K A. Development of heart rate variation over thefirst 6 months of life in normal infants. Pediatr Res 26(4,1989):343-346].

The vagus (or vagal) afferent nerve fibers arise from cell bodieslocated in the vagal sensory ganglia. These ganglia take the form ofswellings found in the cervical aspect of the vagus nerve just caudal tothe skull. There are two such ganglia, termed the inferior and superiorvagal ganglia. They are also called the nodose and jugular ganglia,respectively (See FIG. 1 ). The jugular (superior) ganglion is a smallganglion on the vagus nerve just as it passes through the jugularforamen at the base of the skull. The nodose (inferior) ganglion is aganglion on the vagus nerve located in the height of the transverseprocess of the first cervical vertebra.

Vagal afferents traverse the brainstem in the solitary tract, with someeighty percent of the terminating synapses being located in the nucleusof the tractus solitarius (or nucleus tractus solitarii, nucleus tractussolitarius, or NTS, see FIG. 1 ). The NTS projects to a wide variety ofstructures in the central nervous system, such as the amygdala, raphenuclei, periaqueductal gray, nucleus paragigantocellurlais, olfactorytubercule, locus ceruleus, nucleus ambiguus and the hypothalamus. TheNTS also projects to the parabrachial nucleus, which in turn projects tothe hypothalamus, the thalamus, the amygdala, the anterior insula, andinfralimbic cortex, lateral prefrontal cortex, and other corticalregions [JEAN A. The nucleus tractus solitarius: neuroanatomic,neurochemical and functional aspects. Arch Int Physiol Biochim Biophys99(5, 1991):A3-A52]. Such central projections are discussed below inconnection with the interoception and resting state neural networks.

With regard to vagal efferent nerve fibers, two vagal components haveevolved in the brainstem to regulate peripheral parasympatheticfunctions. The dorsal vagal complex, consisting of the dorsal motornucleus and its connections (see FIG. 1 ), controls parasympatheticfunction primarily below the level of the diaphragm (e.g. gut and itsenterochromaffin cells), while the ventral vagal complex, comprised ofnucleus ambiguus and nucleus retrofacial, controls functions primarilyabove the diaphragm in organs such as the heart, thymus and lungs, aswell as other glands and tissues of the neck and upper chest, andspecialized muscles such as those of the esophageal complex. Forexample, the cell bodies for the preganglionic parasympathetic vagalneurons that innervate the heart reside in the nucleus ambiguus, whichis relevant to potential cardiovascular side effects that may beproduced by vagus nerve stimulation.

With the foregoing as preliminary information about the vagus nerve, thetopics that are presented below in connection with the disclosure of theinvention include the following: (1) Use of the vagus nerve stimulatorto condition the behavior of a child; (2) Overview of physiologicalmechanisms through which the disclosed vagus nerve stimulation methodsmay be used to modulate the neuronal circuitry of individuals withpervasive developmental disorders; (3) Description of Applicant'smagnetic and electrode-based nerve stimulating devices, describing inparticular the electrical waveform used to stimulate a vagus nerve; (4)Preferred embodiments of the magnetic stimulator; (5) Preferredembodiments of the electrode-based stimulator; (6) Application of thestimulators to the neck of the patient; (7) Use of the devices withfeedback and feedforward to improve treatment of individual patients.Use of the vagus nerve stimulator to condition the behavior of a child

The first aspect of the present invention is an application of anearlier invention that we disclosed in a commonly assigned, co-pendingapplication, Ser. No. 13/024,727, entitled Non-invasive methods anddevices for inducing euphoria in a patient and their therapeuticapplication, to SIMON et al, which is incorporated by reference. Asdisclosed in that earlier application, vagus nerve stimulation may beused to create a state of euphoria in an individual. That is to say,with appropriate devices and electrical stimulus parameters, thestimulation can create a euphoric sensation in the stimulatedindividual. This discovery is used in the present invention as aconditioning tool, with which improved behavior on the part of a childis rewarded or positively reinforced. For example, when the childexhibits a desired behavior, such as making eye contact with thetherapist or some other individual, the child is rewarded with euphoricstimulation through the vagus nerve stimulator. When the child is notbehaving in a developmentally desirable fashion, the euphoricstimulation is generally withheld. It is understood that undesirablebehavior could in principle be punished with unpleasant, aversiveelectrical stimulation as well, but such aversive stimuli arediscouraged in the present invention [U.S. Pat. No. 4,440,160, entitledSelf-injurious behavior inhibiting system, to FISCHELL et al.; LICHSTEINK L, Schreibman L. Employing electric shock with autistic children. Areview of the side effects. J Autism Child Schizophr 6(2,1976):163-173].On the other hand, a therapeutically beneficial signal that is neutralwith regard to its sensed pleasantness versus unpleasantness may beadministered alone or in combination with euphoric stimulation, asdescribed in the following section.

Even if the child is to be treated with vagus nerve stimulation that isdirected to neural circuits other than those involved in producing theeuphoria (as disclosed in the following section), the treatment mayordinarily begin with, or be accompanied by, euphoric vagus nervestimulation anyway. The reason is that the children to be treated willoften be uncooperative and will resist the placement and long-termapplication of the noninvasive vagus nerve stimulator on their neck,unless they are motivated to cooperate. The prospect of the euphoricstimulation provides that motivation. However, it is understood thatsome children will always resist the application of a noninvasive vagusnerve stimulator, and for them euphoric conditioning methods might onlybe feasible if a stimulation electrode is implanted about the vagusnerve, or if deep brain stimulation is used instead in an attempt toproduce the euphoric state of mind, but this would ordinarily beundertaken only if there were other primary reasons for performing suchinvasive procedures.

Turning now to the methods of conditioning children with autism oranother developmental disorder—the vagus nerve stimulator, ordinarilysituated in a neck collar, is placed on the child's neck. Such a collarand device will be described below (see FIG. 6B), along with methodsthat compensate for changes in the position of the stimulator relativeto the vagus nerve, for example, as the child moves his neck within thelimits of constraint of the collar. The stimulation parameters thatproduce a euphoric sense are then determined empirically for each child.Control of the stimulator parameters (on/off, frequency, pulse width,etc.) will ordinarily be accomplished remotely, using a controller thatcommunicates with the stimulator wirelessly and that can be adjusted bythe therapist or parent.

The presence or absence of the euphoric vagus nerve stimulation is thencontrolled by the therapist or parent, as required by the situation athand and by the goals of the therapy. Intermediate stimulationmagnitudes may also be used, if different levels of euphoria aredesired. Ordinarily, the therapist or parent will have already indicatedto the child what type of behavior is desired. In general, the therapyis directed towards promoting developmentally appropriate socialinteraction and communication, as well as the absence of restrictedinterests and repetitive behavior. Examples of different categories ofconditioning using the stimulator are as follows.

As an example of treating impairment in the use of non-verbal behaviors,the child is conditioned to improve and increase eye-to-eye gaze withthe therapist or with other individuals. When the autistic child makeseye contact, the euphoric stimulation is applied promptly thereafter,and when eye contact is not made or is lost, the euphoric stimulation ispromptly turned off. Once the euphoric reward for some activity, such asmaking eye contact, has produced a significant result over the course ofprolonged therapy, the reward for that activity may be made lessfrequent or with a reduced amplitude (“fading” or “thinning”, e.g.,stimulate on every other eye contact, or only when making eye contactwith different individuals, etc), unless there is regression on the partof the child.

As an example of improving development of peer relationships, theeuphoric stimulation is applied when the autistic child interacts with achild of roughly the same age, but not when the autistic child interactswith an adult or with a much younger or much older child.

As an example of promoting the sharing of interests with others,euphoric stimulation is applied when there is a demonstration of jointattention, e.g. when the autistic child points to something, to call thetherapist's or parent's attention to that object.

As an example of promoting an increased social reciprocity, euphoricstimulation is applied when the autistic child heeds the suggestion ofanother child.

As an example of promoting the use of spoken or nonverbal language,euphoric stimulation is applied depending on developmental stage, e.g.,when the autistic child uses a spoken word or facial expression orgesture.

As an example of promoting non-repetition of words, euphoric stimulationis applied when the child responds to words spoken to the child, butonly when the response is not simply a repetition of those same words.

As an example of promoting engagement in conversation, euphoricstimulation is applied when the autistic child makes multiple statementsin a conversation, as in statement1, response1, statement2, response2 .. . .

As an example of promoting novelty in pretend play, euphoric stimulationis applied when the autistic child uses of a new doll or object, orplays with the doll or object in a new way.

As an example of promoting interest in a new subject, euphoricstimulation is applied when the autistic child asks a question that isdifferent than a question that has been repeatedly asked and answered inthe past; or when the child takes an interest in a new televisionprogram.

As an example of promoting flexibility in routines or the loss of ritualbehavior, euphoric stimulation is applied when the autistic child doesnot complain that his clothing has a color other than the preferredcolor, or that the drive to the store takes a new route.

As an example of promoting the loss of repetitive or stereotypedbehavior, euphoric stimulation is withheld when the autistic childexhibits stereotypic behavior such as arm flapping, rocking,toe-walking, the assumption of odd postures, etc.

As an example of promoting the loss of preoccupation with particularobjects, euphoric stimulation is withheld when the autistic child linesobjects in a row, opens and closes doors repeatedly, turns lights on andoff repeatedly, transfers water repeatedly from one vessel to another,spins the wheels of a toy repeatedly, etc.

It is understood that positive reinforcement for producingdevelopmentally appropriate behavior is already part of applied behavioranalysis programs that treat autism [VISMARA L A, Rogers S J. Behavioraltreatments in autism spectrum disorder: what do we know? Annu Rev ClinPsychol 6(2010):447-468; WARREN Z, Veenstra-VanderWeele J, Stone W, etal. Therapies for Children With Autism Spectrum Disorders. ComparativeEffectiveness Review No. 26. (Prepared by the Vanderbilt Evidence-basedPractice Center under Contract No. 290-2007-10065-I.) AHRQ PublicationNo. 11-EHCO29-EF. Rockville, Md.: Agency for Healthcare Research andQuality. April 2011, 908 pp]. Perhaps the best known example of suchapplied behavior analysis is the UCLA/Lovaas-based intervention, whichinvolves discrete-trial teaching, breaking skills down into their mostbasic components, then rewarding positive performance with praise andreinforcers. According to the present invention, euphoric vagus nervestimulation may be used as a reinforcer in all such programs, replacingor complementing conventional reinforcers that are already used in suchprograms.

The euphoric stimulation may also be used as a reward in learningprograms for autistic children, when the child has acquired new skillsor knowledge. Advantages in regard to the euphoric stimulation as areinforcer include the properties: that by varying stimulationamplitudes, gradations of euphoric stimulation reinforcement may bepossible (variable or contingent reinforcement); and it is possible touse concomitant or alternating stimulation waveforms that are directedto the particular neural networks that are implicated in autisticbehavior, in addition to the euphoric neural networks. Thus, in apreferred embodiment, the vagus nerve stimulation is not only pleasantto the child and useful for conditioning developmentally appropriatesocial interaction and communication, as well as the absence ofrestricted interests and repetitive behavior, but it may also compensatefor imbalances or other abnormalities in the child's neural networksthat may be responsible for the behavior that is being conditioned, asdescribed in the next section. That is to say, in the preferredembodiment, the vagus nerve stimulator is used not only as a behavioralor educational reinforcer, but also as a medical tool.

Overview of Physiological Mechanisms through which the Disclosed VagusNerve Stimulation Methods may be used to Modulate the Neuronal Circuitryof Individuals with Pervasive Developmental Disorders

We now disclose methods and devices for electrically stimulating a vagusnerve noninvasively, in order to provide medical treatment to anindividual having or developing a pervasive developmental disorder suchas autism. Although the treatment is medical, it should be understood atthe outset that autism is not a disease. It is instead a disorder inwhich anatomical components of the cerebral cortex that are responsiblefor the emergence of cognitive properties do not develop and connect toone another normally.

Neurodevelopmental disorders such as autism are characterized by aseries of missed developmental milestones that would normally occurbefore birth and during early childhood. The natural history of autismmay involve three components: (1) there is an underlying vulnerabilityto the development of the child's brain, particularly a set of geneticabnormalities; (2) there are exogenous stressors; and (3) brainstructures and connections that would normally form at critical timesduring development of the brain do not form normally, resulting in acascade of pathological events that are significantly influenced byenvironmental factors. It is understood that such milestones may beinterpretable ultimately in terms of the spatio-temporal sequences ofgene expression in the developing brain [KANG H J, Kawasawa Y I, ChengF, et al. Spatio-temporal transcriptome of the human brain. Nature478(7370, 2011):483-489].

Underlying brain alterations in autism occur well before correspondingsymptoms are manifest. The initial neuro-developmental disruption thatis responsible for autism may begin as early as embryonic day 40 and isgenerally thought to arise during the first trimester of a pregnancy.Thus, in utero exposure to valproic acid and other anticonvulsantssignificantly increase the risk for manifesting autism or autistic-liketraits postnatally. Other drugs that affect the likelihood of a fetusdeveloping into an autistic child include thalidomide, misoprostol,selective serotonin reuptake inhibitors, cocaine, and ethanol. Rubellaexposure during the first trimester also increases the risk of autism.The timing of the underlying insult (e.g., first trimester) may be ofequal, if not greater importance, than the anatomical loci affected.However, the likelihood of developing autism is also a function ofadditional factors, particularly the genetics of the child[DUFOUR-Rainfray D, Vourc'h P, Tourlet S, Guilloteau D, Chalon S, AndresC R. Fetal exposure to teratogens: evidence of genes involved in autism.Neurosci Biobehav Rev 35(5, 2011):1254-65; MEYER U, Yee B K, Feldon J.The neurodevelopmental impact of prenatal infections at different timesof pregnancy: the earlier the worse? Neuroscientist 13(3,2007):241-256].

Autism has a strong genetic component. Studies of twins suggest thatheritability is as high as 0.9 for autism spectrum disorders, andsiblings of those with autism are about 25 times more likely to beautistic than the general population. Common alleles that increaserelative risk for autism by 2-fold or more have been sought intensely,but alleles of putative risk genes that are found frequently in thepopulation (e.g., MACROD2, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C)have failed to demonstrate such risk. More likely, the genetic roots ofautism trace to hundreds of rare de novo and inherited copy numbervariants, suggesting a key role for gene dosage in susceptibility toautism, often in genes that encode proteins affecting neuronaldevelopment such as those involved in synaptic cell adhesion.

Nevertheless, it is worth testing for abnormal genes that are associatedwith genetic syndromes that may be comorbid with autism, such as FMR1(fragile X syndrome), TSC1 and TSC2 (tuberous sclerosis), PTEN(hamartoma tumor syndrome) and MECP2 (Rett syndrome) [Ravinesh A KUMAR.Genetics of autism spectrum disorders. Curr Neurol Neurosci Rep9(2009):188-197; GESCHWIND D H. Genetics of autism spectrum disorders.Trends Cogn Sci 15(9, 2011):409-416; Judith H. MILES. Autism spectrumdisorders—A genetics review. Genet Med 13(4, 2011):278-294; SHEN Y, DiesK A, Holm I A, et al. Clinical genetic testing for patients with autismspectrum disorders. Pediatrics 125(4, 2010):e727-e735]. Disorders withautistic spectrum features often derive from compromised regulation ofmTOR-linked signaling pathways (mammalian target of rapamycin, mTOR,which is a protein encoded by the FRAP1 gene). Notably, mTOR is the hubof a signaling pathway that includes PTEN, TSC1, and TSC2. ThemTOR-signalling pathways are connected to glutamate signaling pathwaysvia the gene mGluR5.

In view of the likelihood that the brain of an autistic child may miss aseries of neuro-developmental milestones that can occur during onlyduring particular time-windows, both in utero and after birth, aprophylactic intervention that would stop or redirect the abnormaldevelopmental progression should take into account the then-existingdevelopmental state of the child's brain. Once a time-window for aparticular developmental stage has closed, the abnormal brain structuremay have become irreversibly formed, and the intervention to treat theabnormality would be then characterized as an attempt to induce acompensatory structure, function, or loss of function. Accordingly, thepresent invention generally contemplates two types of interventions,prophylactic and compensatory. With a compensatory intervention, thedevelopmental neuroanatomical abnormalities are not prevented, but thefunctional defects arising from such abnormalities are preferablyminimized or reversed using a countermeasure involving vagus nervestimulation [MEREDITH R M, Dawitz J, Kramvis I. Sensitive time-windowsfor susceptibility in neurodevelopmental disorders. Trends Neurosci35(6, 2012):335-344; HENSCH T. K. Critical period plasticity in localcortical circuits. Nature Reviews Neuroscience, 6(2005): 877-888;EHNINGER D, Li W, Fox K, Stryker M P, Silva A J. Reversingneurodevelopmental disorders in adults. Neuron 60(6, 2008):950-960].

Because the earliest stages of abnormal autistic neurodevelopment occurin utero, the invention considers using vagus nerve stimulation of themother, in order to prevent abnormal neurodevelopment of the fetus. Thevagus nerve stimulation is preferably performed during the firsttrimester, in an attempt to modulate the mother's circulating levels ofserotonin (5-HT). The current literature does not discourage such anintervention, because vagus nerve stimulation of a pregnant mother doesnot have any known deleterious effect on the developing fetus, at leastas it is ordinarily performed [HUSAIN M M, Stegman D, Trevino K.Pregnancy and delivery while receiving vagus nerve stimulation for thetreatment of major depression: a case report. Ann Gen Psychiatry4(2005):16, pp. 1-7; HOUSER M V, Hennessy M D, Howard B C. Vagal nervestimulator use during pregnancy for treatment of refractory seizuredisorder. Obstet Gynecol 115(2 Pt 2, 2010):417-419].

Pregnant women who are taking serotonin reuptake inhibitors are atincreased risk of having an autistic child. Cocaine, which is acompetitive antagonist of the serotonin transporter and has an actionsimilar to selective serotonin reuptake inhibitors, is also asignificant risk factor for autism [CROEN L A, Grether J K, Yoshida C K,Odouli R, Hendrick V. Antidepressant use during pregnancy and childhoodautism spectrum disorders. Arch Gen Psychiatry 68(11, 2011):1104-1112;DAVIS E, Fennoy I, Laraque D, Kanem N, Brown G, Mitchell J. Autism anddevelopmental abnormalities in children with perinatal cocaine exposure.J Natl Med Assoc 84(4,1992):315-319]. Consequently, to the extent that adepressed pregnant women use vagus nerve stimulation in lieu of takingserotonin reuptake inhibitors or cocaine to treat depression, that inand of itself may be considered to be an intervention to prevent autismin the child.

Vagus nerve stimulation may also be used to prevent autism in pregnantwomen irrespective of whether they are taking serotonin reuptakeinhibitors or cocaine. This is because the known role of 5-HT in braindevelopment raises the possibility that increased 5-HT levels reachingthe fetus via the placenta may result in more normal neuronal migrationor neurite outgrowth. In fact, in the earliest stages of development,almost all of the fetus's serotonin comes from the mother, although somemight also come from de novo synthesis from tryptophan in the placentaitself [COTE F, Fligny C, Bayard E, Launay J M, Gershon M D, Mallet J,Vodjdani G. Maternal serotonin is crucial for murine embryonicdevelopment. Proc Natl Acad Sci USA. 2007 Jan. 2; 104(1, 2007):329-334].

Approximately 90% of the human body's total serotonin is located in theenterochromaffin cells in the gut, where it is used to regulateintestinal movements and control circulating serotonin levels. Releaseof the serotonin from the enterochromaffin cells is regulated by thevagus nerve, and its release into the portal circulation is controlledby vagal efferent adrenergic nerve fibers [GRONSTAD K O, Zinner M J,Nilsson O, Dahlström A, Jaffe B M, Ahlman H. Vagal release of serotonininto gut lumen and portal circulation via separate control mechanisms. JSurg Res 44(2,1988):146-151; PETTERSSON G. The neural control of theserotonin content in mammalian enterochromaffin cells. Acta PhysiolScand Suppl 470(1979):1-30]. Thus, by electrically stimulating the vagusnerve in such a way as to increase the activity of vagal efferentadrenergic nerve fibers, the release of serotonin into the circulationof the mother and placenta will also be increased. The mechanism isillustrated in FIG. 1 and is described more completely in pararagraphsbelow.

Stimulation of the cervical (or thoracic) vagus nerve at the site shownin the FIG. 1 causes the release of serotonin into the gut by acholinergic pathway, and into the portal circulation by an adrenergicpathway. The adrenergic pathway is abolished when the superior cervicalsympathetic ganglia are removed. The adrenergic nerve stimulation may bedirect, along efferent vagus nerve fibers, or it may be indirect whereinafferent vagal fibers are stimulated that indirectly increase theactivity of the efferent adrenergic nerve fibers via central feedbackmechanisms involving loops in the neural circuitry shown in FIG. 1 ,through the intermediolateral nucleus of the spinal cord. We note thatsimilar effects might be obtained by electrically simulating thesplanchnic nerve [LARSSON I, Ahlman H, Bhargava H N, Dahlström A,Pettersson G, Kewenter J. The effects of splanchnic nerve stimulation onthe plasma levels of serotonin and substance P in the portal vein of thecat. J Neural Transm 46(2,1979):102-112].

Almost all of the serotonin that is released into the portal circulationis sequestered by platelets via serotonin transporters. The plateletsare thought to release the serotonin in the placenta, whereupon thematernal serotonin is actively transported through the placental brushborder cells via serotonin transporters [COTE F, Fligny C, Bayard E,Launay J M, Gershon M D, Mallet J, Vodjdani G. Maternal serotonin iscrucial for murine embryonic development. Proc Natl Acad Sci USA. 2007Jan. 2; 104(1, 2007):329-334; YAVARONE M S, Shuey D L, Sadler T W,Lauder J M. Serotonin uptake in the ectoplacental cone and placenta ofthe mouse. Placenta 14(2,1993):149-161]. If the mother is takingserotonin reuptake inhibitors that target the serotonin transporter,then the platelet sequestration and placental transport of serotoninwill be reduced, such that there would be decreased availability ofserotonin to the developing fetus. Thus, the platelets would thencontain abnormally low levels of serotonin, and the transport ofserotonin across the placenta would also be reduced. In such asituation, the vagus nerve stimulation is an intervention to increasethe maternal circulating levels of serotonin as compensation for theinactivity of the serotonin transporters, brought about by the use ofserotonin reuptake inhibitors or cocaine.

The opposite problem may occur in families that are geneticallypredisposed to autism by virtue of a mutation in the serotonintransporter, wherein the problem lies not in the difficulty of gettingserotonin into the platelet, but in the difficulty of getting serotoninout of the platelet (as well as out of a presynaptic nerve body andacross a synapse). In that case, the serotonin transporter isoveractive, such that the platelets will develop abnormally high levelsof serotonin, because the overactive transporter antagonizes,counteracts or reabsorbs any release of serotonin from the platelets[VEENSTRA-VanderWeele J, Muller C L, Iwamoto H, et al. Autism genevariant causes hyperserotonemia, serotonin receptor hypersensitivity,social impairment and repetitive behavior. Proc Natl Acad Sci USA109(14, 2012):5469-5474]. In such a case, the use of serotonin reuptakeinhibitors may actually be useful. Vagus nerve stimulation of the mothermay still also be helpful, in an effort to down-regulate the productionof the overactive maternal serotonin transporters. Thus, the synthesisof serotonin transporters is a function of the plasma serotoninconcentration, such that at the relatively high levels of plasmaserotonin that would be induced by vagus nerve stimulation, theproduction of maternal serotonin transporters would be inhibited, sothat less of any released serotonin could be reabsorbed [MERCADO C P,Kilic F. Molecular mechanisms of SERT in platelets: regulation of plasmaserotonin levels. Mol Intery 10(4, 2010):231-241].

It is advisable to confirm that the maternal and fetal genetics areconsistent with such an autism gene variant, because there are potentialcauses of elevated circulating serotonin levels in autistic individuals,other than the heritable overactive serotonin transporter that isassociated with the autism-related variant serotonin transporter gene[JANUSONIS S. Origin of the blood hyperserotonemia of autism. Theor BiolMed Model 22(2008);5:10, pp 1-16]. Otherwise, the vagus nervestimulation might not have its intended effect [WHITAKER-Azmitia P M.Behavioral and cellular consequences of increasing serotonergic activityduring brain development: a role in autism? Int J Dev Neurosci 23(1,2005):75-83]. Thus, after an analysis like that described by JANUSONIS,it may be concluded that the mother's circulating serotonin levels wouldbest be decreased. In that case, by electrically stimulating the vagusnerve in such a way as to decrease the activity of vagal efferentadrenergic nerve fibers through application of blocking or inhibitingelectrical pulses (directly or indirectly via central feedbackmechanisms), the release of serotonin into the circulation of the motherand placenta would be decreased.

Another caveat is the following. Because serotonin does not cross theblood-brain barrier, this intervention would not be expected to lead tocognitive side effects in the mother, but because serotonin levelsaffect blood pressure and have other cardiovascular effects, those sideeffects should be anticipated and possibly treated [WATTS S W, MorrisonS F, Davis R P, Barman S M. Serotonin and blood pressure regulation.Pharmacol Rev 64(2, 2012):359-388].

A prophylactic or compensatory intervention involving electricalstimulation of the fetus itself is also conceivable, becauseembryogenesis makes use of endogenously produced electric fields, andexternally applied electric fields have been used experimentally tomodulate embryogenesis [Colin LOWRY. The Electric Embryo: How ElectricFields Mold the Embryo's Growth Pattern and Shape, 21st Century Science& Technology, Spring 1999, pp. 56-70]. Such externally appliedelectromagnetic fields have apparently never been considered inconnection with preventing autism. The only investigations concerningthe effect of endogenous electric fields on developing fetuses, as itrelates to autism, have dealt with safety and mechanism issues, such aswhether fetal brain tissue can demodulate microwave radiation at 217 Hzvia oscillation of magnetite crystals [Richard LATHE. Microwaveelectromagnetic radiation and autism. Electronic Journal of AppliedPsychology: Innovations in Autism. 5(1, 2009):11-30].

If treatment of the potentially autistic child does not begin in utero,then prophylactic or compensatory treatment could begin shortly afterthe birth of the child. In order to justify treating a newborn, theremust be a reasonable likelihood that the child is or will becomeautistic. If a sibling has already been diagnosed with autism, thelikelihood that the newborn is or will be autistic is significantlyincreased. At some point, it may even become possible to predictneuro-developmental abnormalities at birth through a comprehensiveanalysis of a placental or neonatal genetics [KNICKMEYER R C, Wang J,Zhu H, Geng X, Woolson S, Hamer R M, Konneker T, Lin W, Styner M,Gilmore J H. Common Variants in Psychiatric Risk Genes Predict BrainStructure at Birth. Cereb Cortex. 2013 Jan. 2. (Epub ahead of print)].However, it is currently difficult to diagnose autistic children beforethe age of two on the basis of behavior alone, by which time manyneuro-developmental time-windows may have already closed. One problem inthat regard is that some children behave normally shortly after birth,but retrogress after a year or more (false negatives). Another problemis that the child may have a different problem, such as retardation(false positives). It has been proposed that the best behavioralpredictors of autism in infants are the frequency with which the childlooked at other person, the abnormal ability to disengage and move hisfocus of attention, neonatal auditory brainstem responses, and 4-montharousal-modulated attention visual preference [STONE W L, Lee E B,Ashford L, Brissie J, Hepburn S L, Coonrod E E, Weiss B H. Can autism bediagnosed accurately in children under 3 years? J Child PsycholPsychiatry 40(2,1999):219-226; WERNER E, Dawson G, Osterling J, Dinno N.Brief report: Recognition of autism spectrum disorder before one year ofage: a retrospective study based on home videotapes. J Autism Dev Disord30(2, 2000):157-162; ZWAIGENBAUM L, Bryson S, Rogers T, Roberts W, BrianJ, Szatmari P. Behavioral manifestations of autism in the first year oflife. Int J Dev Neurosci 23(2-3, 2005):143-152; OSTERLING J A, Dawson G,Munson J A. Early recognition of 1-year-old infants with autism spectrumdisorder versus mental retardation. Dev Psychopathol 14(2,2002):239-251; BRYSON S E, Zwaigenbaum L, McDermott C, Rombough V, BrianJ. The Autism Observation Scale for Infants: scale development andreliability data. J Autism Dev Disord 38(4, 2008):731-738; JOHNSON C P.Recognition of autism before age 2 years. Pediatr Rev 29(3, 2008):86-96;COHEN I L, Gardner J M, Karmel B Z, Phan H T, Kittler P, Gomez T R,Gonzalez M G, Lennon E M, Parab S, Barone A. Neonatal Brainstem Functionand 4-Month Arousal-Modulated Attention Are Jointly Associated WithAutism. Autism Res. 2012 Nov. 16. (Epub ahead of print)].

The suspicion of autism in a newborn may be confirmed or contradicted tosome extent with evidence provided by biomarker data [WALSH P, ElsabbaghM, Bolton P, Singh I. In search of biomarkers for autism: scientific,social and ethical challenges. Nat Rev Neurosci 12(10, 2011):603-612;VEENSTRA-VanderWeele J, Blakely R D. Networking in autism: leveraginggenetic, biomarker and model system findings in the search for newtreatments. Neuropsychopharmacology 37(1, 2012):196-212; RATAJCZAK HV.Theoretical aspects of autism: biomarkers—a review. J Immunotoxicol 8(1,2011):80-94; HENDREN R L, Bertoglio K, Ashwood P, Sharp F. Mechanisticbiomarkers for autism treatment. Med Hypotheses 73(6, 2009):950-954;SKJELDAL O H, Sponheim E, Ganes T, Jellum E, Bakke S. Childhood autism:the need for physical investigations. Brain Dev 20(4,1998):227-233].Genetic biomarkers were mentioned above, which would be considered inconjunction with family history. Another consideration is the anatomy ofthe child's brain. Diffusion tensor imaging may be used to evaluatewhether aberrant development of white matter pathways is present in thebrain of a 6-month old child, which appears to be a useful predictor ofwhether the child will become diagnosed with autism [WOLFF J J, Gu H,Gerig G, et al. Differences in white matter fiber tract developmentpresent from 6 to 24 months in infants with autism. Am J Psychiatry169(6, 2012):589-600].

Another useful biomarker that was mentioned above has been recognizedfor over 50 years—elevated whole-blood serotonin (5-HT), which is uniqueto autism among developmental disorders. Although circulating 5-HT willnot cross the blood-brain barrier of the newborn, it is presumed thatthe protein networks regulating peripheral 5-HT homeostasis areconserved in the brain, such that serotonergic raphe nuclei of thebrain, which release serotonin to the rest of the brain, may be likewiseabnormal. Changes in brain 5-HT homeostasis during development of thenewborn's brain may then result in altered neuronal migration or neuriteoutgrowth that contributes to autism. Accordingly, in one aspect of theinvention, vagus nerve stimulation of the newborn or infant is intendedto increase the activity of raphe nuclei (see FIG. 1 ) to produce moreserotonin in the newborn's brain, among those newborns who havedemonstrable hyper-serotonemia due to an overactive serotonintransporter that is associated with an autism-related variant serotonintransporter gene, especially if they are also considered to be at highrisk of developing autism for other reasons [Adrienne E. DORR and GuyDebonnel. Effect of vagus nerve stimulation on serotonergic andnoradrenergic transmission. J Pharmacol Exp Ther 318(2, 2006):890-898;MANTA S, Dong J, Debonnel G, Blier P. Enhancement of the function of ratserotonin and norepinephrine neurons by sustained vagus nervestimulation. J Psychiatry Neurosci 34(4, 2009):272-280; MANTA S, ElMansari M, Blier P. Novel attempts to optimize vagus nerve stimulationparameters on serotonin neuronal firing activity in the rat brain. BrainStimul 5(3, 2012):422-429].

The brain size at 6 months is not a good predictor of whether an infanthas or will develop autism [HAZLETT H C, Gu H, McKinstry R C, et al.Brain volume findings in 6-month-old infants at high familial risk forautism. Am J Psychiatry 169(6, 2012):601-608]. On the other hand, inautistic children, the brain undergoes a period of precocious growthduring early postnatal life followed by a deceleration in age-relatedgrowth, such that the rate of growth of the brain in infants is arecognized biomarker for autism [COURCHESNE E, Carper R, Akshoomoff N.Evidence of brain overgrowth in the first year of life in autism. JAMA290(2003): 337-344; DAWSON G, Munson J, Webb S J, Nalty T, Abbott R,Toth K. Rate of head growth decelerates and symptoms worsen in thesecond year of life in autism. Biol Psychiatry 61(4, 2007):458-464].

A variety of candidate processes have been proposed to explain brainovergrowth and deceleration in autistic children, most of which focus onfactors that affect the rate of neuronal development. However, the morelikely explanation is that autistic children not only have an unusualpattern of brain growth and deceleration, but they also have a moregeneral pattern of whole body (e.g., skeletal and body weight)overgrowth followed by deceleration [CHAWARSKA K, Campbell D, Chen L,Shic F, Klin A, Chang J. Early generalized overgrowth in boys withautism. Arch Gen Psychiatry 68(10, 2011):1021-1031]. Accordingly, thereappears to be an abnormality of growth stimulating factors during thechild's first year, followed by a reversal of such factors in the secondyear (e.g., FGF-2, IGF-1, BDNF, and VEGF). Furthermore, serotonin, whichis often held at elevated levels in the platelets of individuals withautism, has an important role not only in neuronal development, but alsoin bone and skeletal development. In fact, brain overgrowth in autism iscorrelated with the unusual variant of the serotonin transporter inautistic children [WASSINK T H, Hazlett H C, Epping E A, Arndt S, DagerS R, Schellenberg G D, Dawson G, Piven J. Cerebral cortical gray matterovergrowth and functional variation of the serotonin transporter gene inautism. Arch Gen Psychiatry 64(2007):709-717]. As noted above, thebiochemistry of autism may involve defects surrounding the gene mTOR,which is the hub of a signaling pathway that includes PTEN and that isconnected to glutamate signaling pathways via the gene mGluR5. It istherefore noteworthy that the autism-related serotonin transporterallele works with PTEN to influence brain size [PAGE D T, Kuti O J,Prestia C, Sur M. Haploinsufficiency for Pten and serotonin transportercooperatively influences brain size and social behavior. Proc Natl AcadSci USA 106(2009): 1989-1994].

Therefore, in another aspect of the invention, vagus nerve stimulationis used as a prophylaxis or countermeasure against unusual patterns ofgrowth during the first and second years, through modulation of growthfactors such as those mentioned above. BDNF appears to be involved inregulating key aspects of both metabolism and energy balance. Vagusnerve stimulation has been observed to simultaneously increase BDNFlevels and decrease body weight. It also activates BDNF receptor TrkB[BANNI S, Carta G, Murru E, Cordeddu L, Giordano E, Marrosu F,Puligheddu M, Floris G, Asuni G P, Cappai A L, Deriu S, Follesa P. Vagusnerve stimulation reduces body weight and fat mass in rats. PLoS One7(9, 2012):e44813, pp. 1-10; FURMAGA H, Carreno F R, Frazer A. Vagalnerve stimulation rapidly activates brain-derived neurotrophic factorreceptor TrkB in rat brain. PLoS One 7(5, 2012):e34844, pp. 1-10].Consequently, to the extent that an insufficiency in BDNF levels oractivity contribute to the body overgrowth seen in autistic childrenduring the first year, vagus nerve stimulation of the infant maysimultaneously increase the BNDF levels and activity and counteract theabnormal growth rate of autistic infants. The vagus nerve stimulationmay also induce an increased expression of other growth factors, such asFGF-2, which may likewise promote a more normal growth rate pattern inautistic children [FOLLESA P, Biggio F, Gorini G, Caria S, Talani G,Dazzi L, Puligheddu M, Marrosu F, Biggio G. Vagus nerve stimulationincreases norepinephrine concentration and the gene expression of BDNFand bFGF in the rat brain. Brain Res 1179(2007):28-34]. Hepatocytegrowth factor/scatter factor (HGF/SF) is another growth factor that isimplicated in autism and that might be modulated by vagus nervestimulation [LEVITT P. Disruption of interneuron development. Epilepsia46(Suppl 7, 2005):22-28]. In regards to the manipulation of serotoninlevels to promote a more normal growth rate, this may be done bymodulating the activity of raphe nuclei in the infant's brain with vagusnerve stimulation, as described above.

Two more growth factor levels that might be modulated by vagus nervestimulation, members of the fibroblast growth factor family FGF-22 andFGF-7, are known to influence the balance between excitation andinhibition in the brain, respectively, by promoting the organization ofexcitatory and inhibitory presynaptic terminals through activation ofdifferent signaling pathways via their specific receptors [TERAUCHI A,Johnson-Venkatesh E M, Toth A B, Javed D, Sutton M A, Umemori H.Distinct FGFs promote differentiation of excitatory and inhibitorysynapses. Nature 465(7299, 2010):783-787; TERAUCHI A, Umemori H.Specific sets of intrinsic and extrinsic factors drive excitatory andinhibitory circuit formation. Neuroscientist 18(3, 2012):271-286]. Theneurodevelopmental abnormalities in autism are thought to produce animbalance between excitatory and inhibitory neurons, giving rise toinappropriate excitation [RUBENSTEIN J L, Merzenich M M. Model ofautism: increased ratio of excitation/inhibition in key neural systems.Genes Brain Behav 2(5, 2003):255-267]. Much of what is known about suchexcitation-inhibition imbalance comes from investigating the role ofgenes that cause Fragile X and Rett syndromes, whose carriers oftenexperience autistic-like symptoms. Fragile X syndrome is a disease ofexcitation-dominance, whereas in Rett syndrome the balance betweencortical excitation and inhibition is shifted to favor inhibition overexcitation.

To understand the mechanisms and consequences of excitation-inhibitionimbalance in autism, consider that the cerebral cortex consists of twomain classes of neurons, pyramidal cells and interneurons, whichrespectively use glutamate and c-aminobutyric acid (GABA) as their mainneurotransmitters. In the adult cortex, pyramidal cells are excitatorywhile GABA-containing (GABAergic) interneurons are typically inhibitory.There are many subtypes of GABA-containing interneurons. Minicolumnsrepresent the cellular and functional organization of glutamatergic andGABAergic neurons in the cerebral cortex, which are anatomicallycharacterized by vertical arrays of pyramidal neurons with theirdentrides and axon projections. Pyramidal cells arrays are accompaniedby their GABAergic interneurons that establish synapses with pyramidalcells bodies, their axon emergences and dentrites. A narrowing ofcortical minicolumns (i.e., a reduced distance between columns) has beenshown in autistic patients. This reduced intercolumnar distance isthought to depend on structural/anatomical defects in GABAergicinterneurons surrounding principal pyramidal cortical neurons [AMRAL DG, Schumann C M, Nordahl C W. Neuroanatomy of autism. Trends Neurosci31(3, 2008):137-145; CASANOVA M F. The neuropathology of autism. BrainPathol 17(4, 2007):422-433; PICKETT J, London E. The neuropathology ofautism: a review. J Neuropathol Exp Neurol 64(11, 2005):925-935].

In autism, mutations that increase the activity or number of glutamatereceptors, that increase the amount of glutamate in the synapse, or thatamplify glutamate-mediated synaptic potentiation can increase theexcitatory state of the brain. This may involve defects surrounding thegene mTOR, which is the hub of a signaling pathway that includes PTENand that is connected to glutamate signaling pathways via the genemGluR5. Likewise, mutations that increase the activity or number of GABAreceptors, that increase the amount of GABA in the synapse, or thatamplify GABA-mediated synaptic potentiation can decrease the excitatorystate of the brain. GABAergic inhibition can be affected in two ways,presynaptically by a reduction in GABA release into the synapse orpostsynaptically by an alteration in GABA receptor function. This mayinvolve, for example, defects in the GABA-A receptor [GATTO C L, BroadieK. Genetic controls balancing excitatory and inhibitory synaptogenesisin neurodevelopmental disorder models. Front Synaptic Neurosci2(2010):4, pp. 1-19; Rocco PIZZARELLI and Enrico Cherubini. Alterationsof GABAergic signaling in autism spectrum disorders. Neural Plasticity2011: Article 297153, pp. 1-12; RAMAMOORTHI K, Lin Y. The contributionof GABAergic dysfunction to neurodevelopmental disorders. Trends Mol Med17(8, 2011):452-462]. However, many other types of genes are now knownto play a role in the balance between the formation of excitatory andinhibitory synapses, mutations in any of which could contribute toautism. This is because synaptogenesis is a highly controlled process,involving a vast array of players which include cell adhesion molecules,scaffolding and signaling proteins, neurotransmitter receptors andproteins associated with the synaptic vesicle machinery (e.g.,fibroblast growth factors, neuroligins, ephrins/Ephs, netrin-G ligands,LRRTMs, SynCAMs, and Wnts) [LEVINSON J N, El-Husseini A. New players tipthe scales in the balance between excitatory and inhibitory synapses.Mol Pain 23(2005);1:12, pp. 1-6].

The initial formation of GABAergic synapses is thought to be independentof neuronal activity, occurring through elaborate cell-cell recognitionprocesses mediated by transmembrane cell adhesion molecules such asneurexin and neuroligin family members. However, postnatal developmentof synapses in brain regions such as the primary sensory cortex ismodified by neuronal activity and sensory experience, such that thenumber and strength of glutamatergic and GABAergic synapses dynamicallychange in response to neural activity. The number of glutamatergicsynapses appears to be controlled by relative activity among neurons,but the number of GABAergic synapses appears to be dependent on generalactivity [LETO K, Bartolini A, Rossi F. Development of cerebellarGABAergic interneurons: origin and shaping of the “minibrain” localconnections. Cerebellum 7(4, 2008):523-529; TERAUCHI A, Umemori H.Specific sets of intrinsic and extrinsic factors drive excitatory andinhibitory circuit formation. Neuroscientist 18(3, 2012):271-286; DORRNA L, Yuan K, Barker A J, Schreiner C E, Froemke R C. Developmentalsensory experience balances cortical excitation and inhibition. Nature465(7300, 2010):932-936; BURRONE J, O'Byrne M, Murthy V N. 2002.Multiple forms of synaptic plasticity triggered by selective suppressionof activity in individual neurons. Nature 420:414-418; HARTMAN K N, PalS K, Burrone J, Murthy V N. Activity-dependent regulation of inhibitorysynaptic transmission in hippocampal neurons. Nat Neurosci 9(5,2006):642-649].

Consequently, it is disclosed that vagus nerve stimulation shortly afterbirth may be used to increase the number of inhibitory GABAergicsynapses throughout the developing brain, so as to promoteexcitation-inhibition balance in a child that is, or would become,autistic with an excitation imbalance. The stimulation may beaccompanied by other modalities of sensory stimulation, such as sound,successive pictures of faces, etc. Such nerve stimulation is intended tocounteract neuronal inactivity during development, which would lead toreduced inhibition. However, because the resulting specific synapticchanges depend on the developmental stage at which the stimulation isperformed, it is important that the stimulation be performed as soonafter birth as it is determined that the child will likely becomeautistic, then continue at least to approximately the age of two, whensynaptic modification would be most efficacious. After approximately twoyears of age, the effect of vagus nerve stimulation may have more to dowith the inhibition of synaptic pruning than the formation of inhibitorysynapses. The parameters of the vagus nerve stimulation may be selectedor adjusted in such a way as to prevent or reduce abnormal highfrequency components in the EEG of the child, which is a measure ofexcitation-inhibition imbalance [YIZHAR O, Fenno L E, Prigge M, et al.Neocortical excitation/inhibition balance in information processing andsocial dysfunction. Nature 477(7363, 2011):171-178; OREKHOVA, E. V. etal. Excess of high frequency electroencephalogram oscillations in boyswith autism. Biol. Psychiatry 62(2007):1022-1029; CORNEW L, Roberts T P,Blaskey L, Edgar J C. Resting-state oscillatory activity in autismspectrum disorders. J Autism Dev Disord 42(9, 2012):1884-1894]. Thosehigh frequency oscillations are also an indication of excessiveshort-range neural connections and insufficient long rang neuralconnections, as described below in connection with resting statenetworks. Some randomness in the vagus nerve stimulation parameters mayalso be introduced in order to promote differential development ofGABAergic synapses, exploiting the tendency of glutamatergic synapses tobe controlled by relative activity among neurons, but with the number ofGABAergic synapses being dependent on general activity.

For children and adults who already exhibit autistic behavior, thetime-window for the balancing intervention described above might beclosing. Nevertheless, stimulation of the vagus nerve may be helpful forthem as well, but in this case the promotion of inhibition may involveneurotransmitters in addition to GABA. Even in such a case, parametersof the vagus nerve stimulation may be selected or adjusted in such a wayas to prevent or reduce abnormal high frequency components in the EEG ofthe individual, which is used as a measure of excitation-inhibitionimbalance. Excitatory nerves within the dorsal vagal complex generallyuse glutamate as their neurotransmitter. To inhibit neurotransmissionwithin the dorsal vagal complex, the present invention makes use of thebidirectional connections that the nucleus of the solitary tract (NTS)has with structures that produce inhibitory neurotransmitters, or itmakes use of connections that the NTS has with the hypothalamus, whichin turn projects to structures that produce inhibitoryneurotransmitters. The inhibition is produced as the result of thestimulation waveforms that are described below. Thus, acting inopposition to glutamate-mediated activation by the NTS of the areapostrema and dorsal motor nucleus are: GABA, and/or serotonin, and/ornorepinephrine from the periaqueductal gray, raphe nucei, and locuscoeruleus, respectively. FIG. 1 shows how those excitatory andinhibitory influences combine to modulate the output of the dorsal motornucleus. Similar influences combine within the NTS itself, and thecombined inhibitory influences on the NTS and dorsal motor nucleusproduce a general inhibitory effect.

The activation of inhibitory circuits in the periaqueductal gray, raphenucei, and locus coeruleus by the hypothalamus or NTS may also causecircuits connecting each of these structures to modulate one another.Thus, the periaqueductal gray communicates with the raphe nuclei andwith the locus coeruleus, and the locus coeruleus communicates with theraphe nuclei, as shown in FIG. 1 [PUDOVKINA O L, Cremers T I, WesterinkB H. The interaction between the locus coeruleus and dorsal raphenucleus studied with dual-probe microdialysis. Eur J Pharmacol7(2002);445(1-2):37-42.; REICHLING D B, Basbaum A I. Collateralizationof periaqueductal gray neurons to forebrain or diencephalon and to themedullary nucleus raphe magnus in the rat. Neuroscience 42(1,1991):183-200; BEHBEHANI M M. The role of acetylcholine in the functionof the nucleus raphe magnus and in the interaction of this nucleus withthe periaqueductal gray. Brain Res 252(2, 1982):299-307].

In another embodiment of the invention, vagus nerve stimulation is usedto modulate the activity of particular neural networks known as restingstate networks, many of which are thought to be abnormal in individualswith autism. The individual may be a child or an adult. A neural networkin the brain is accompanied by oscillations within the network. Lowfrequency oscillations are likely associated with connectivity at thelargest scale of the network, while higher frequencies are exhibited bysmaller sub-networks within the larger network, which may be modulatedby activity in the slower oscillating larger network. The defaultnetwork, also called the default mode network (DMN), default statenetwork, or task-negative network, is one such network that ischaracterized by coherent neuronal oscillations at a rate lower than 0.1Hz. Other large scale networks also have this slow-wave property, asdescribed below [BUCKNER R L, Andrews-Hanna J R, Schacter D L. Thebrain's default network: anatomy, function, and relevance to disease.Ann NY Acad Sci 1124(2008):1-38; PALVA J M, Palva S. Infra-slowfluctuations in electrophysiological recordings,blood-oxygenation-level-dependent signals, and psychophysical timeseries. Neuroimage 62(4, 2012):2201-2211; STEYN-ROSS M L, Steyn-Ross DA, Sleigh J W, Wilson M T. A mechanism for ultra-slow oscillations inthe cortical default network. Bull Math Biol 73(2, 2011):398-416].

The default mode network corresponds to task-independent introspection(e.g., daydreaming), or self-referential thought. When the DMN isactivated, the individual is ordinarily awake and alert, but the DMN mayalso be active during the early stages of sleep and during conscioussedation. During goal-oriented activity, the DMN is deactivated and oneor more of several other networks, so-called task-positive networks(TPN), are activated. DMN activity is attenuated rather thanextinguished during the transition between states, and is observed,albeit at lower levels, alongside task-specific activations. Strength ofthe DMN deactivation appears to be inversely related to the extent towhich the task is demanding. Thus, DMN has been described as atask-negative network, given the apparent antagonism between itsactivation and task performance. The posterior cingulate cortex (PCC)and adjacent precuneus and the medial prefrontal cortex (mPFC) are thetwo most clearly delineated regions within the DMN [RAICHLE M E, SnyderA Z. A default mode of brain function: a brief history of an evolvingidea. Neuroimage 37(4, 2007):1083-1090; BROYD S J, Demanuele C, DebenerS, Helps S K, James C J, Sonuga-Barke E J. Default-mode braindysfunction in mental disorders: a systematic review. Neurosci BiobehavRev 33(3, 2009):279-96; BUCKNER R L, Andrews-Hanna J R, Schacter D L.The brain's default network: anatomy, function, and relevance todisease. Ann NY Acad Sci 1124(2008):1-38; BUCKNER R L, Sepulcre J,Talukdar T, Krienen F M, Liu H, Hedden T, Andrews-Hanna J R, Sperling RA, Johnson K A. Cortical hubs revealed by intrinsic functionalconnectivity: mapping, assessment of stability, and relation toAlzheimer's disease. J Neurosci 29(2009):1860-1873; GREICIUS M D,Krasnow B, Reiss AL, Menon V. Functional connectivity in the restingbrain: a network analysis of the default mode hypothesis. Proc Natl AcadSci USA 100(2003): 253-258].

For autistic individuals, default mode network activity is abnormal,because it is uncommonly low at rest, with reduced connectivity betweenanterior and posterior regions of the network probably reflecting adisturbance of self-referential thought. Furthermore, the absence of ananti-correlation between the default mode network and task-positivenetworks suggests an imbalance in the toggling between networks, drivenby a paucity of introspective thought in autistic individuals. Thesubcomponents within the default mode network of autistic individualsalso appear to be very weakly connected to one another [BROYD S J,Demanuele C, Debener S, Helps S K, James C J, Sonuga-Barke E J.Default-mode brain dysfunction in mental disorders: a systematic review.Neurosci Biobehav Rev 33(3, 2009):279-296; CHERKASSKY V L, Kana R K,Keller T A, Just M A. Functional connectivity in a baselineresting-state network in autism. Neuroreport 17(16, 2006):1687-1690;ASSAF M, Jagannathan K, Calhoun V D, Miller L, Stevens M C, Sahl R,O'Boyle J G, Schultz R T, Pearlson G D. Abnormal functional connectivityof default mode sub-networks in autism spectrum disorder patients.Neuroimage 53(1, 2010):247-256; KENNEDY D P, Redcay E, Courchesne E.Failing to deactivate: resting functional abnormalities in autism. ProcNatl Acad Sci USA 103(21, 2006): 8275-8280].

The term low frequency resting state networks (LFRSN or simply RSN) isused to describe both the task-positive and task-negative networks.Using independent component analysis (ICA) and related methods to assesscoherence of fMRI Blood Oxygenation Level Dependent Imaging (BOLD)signals in terms of temporal and spatial variation, as well asvariations between individuals, low frequency resting state networks inaddition to the DMN have been identified, corresponding to differenttasks or states of mind. They are related to their underlying anatomicalconnectivity and replay at rest the patterns of functional activationevoked by the behavioral tasks. That is to say, brain regions that arecommonly recruited during a task are anatomically connected and maintainin the resting state (in the absence of any stimulation) a significantdegree of temporal coherence in their spontaneous activity, which iswhat allows them to be identified at rest [SMITH S M, Fox P T, Miller KL, Glahn D C, Fox P M, et al. Correspondence of the brain's functionalarchitecture during activation and rest. Proc Natl Acad Sci USA106(2009): 13040-13045].

Frequently reported resting state networks (RSNs), in addition to thedefault mode network, include the sensorimotor RSN, the executivecontrol RSN, up to three visual RSNs, two lateralized fronto-parietalRSNs, the auditory RSN and the temporo-parietal RSN. However, differentinvestigators use different methods to identify the low frequencyresting state networks, so different numbers and somewhat differentidentities of RSNs are reported by different investigators [COLE D M,Smith S M, Beckmann C F. Advances and pitfalls in the analysis andinterpretation of resting-state FMRI data. Front Syst Neurosci4(2010):8, pp.1-15]. Examples of RSNs are described in publicationscited by COLE and the following: ROSAZZA C, Minati L. Resting-statebrain networks: literature review and clinical applications. Neurol Sci32(5, 2011):773-85; ZHANG D, Raichle M E. Disease and the brain's darkenergy. Nat Rev Neurol 6(1, 2010):15-28; DAMOISEAUX, J. S., Rombouts, S.A. R. B., Barkhof, F., Scheltens, P., Stam, C. J., Smith, S. M.,Beckmann, C. F. Consistent resting-state networks across healthysubjects. Proc. Natl. Acad. Sci. U.S.A. 103(2006): 13848-13853 FOX M D,Snyder A Z, Vincent J L, Corbetta M, Van Essen D C, Raichle M E. Thehuman brain is intrinsically organized into dynamic, anticorrelatedfunctional networks. Proc Natl Acad Sci USA102(2005):9673-9678; L I R,Wu X, Chen K, Fleisher A S, Reiman E M, Yao L. Alterations ofDirectional Connectivity among Resting-State Networks in AlzheimerDisease. AJNR Am J Neuroradiol. 2012 Jul. 12. [Epub ahead of print, pp.1-6].

For example, the dorsal attention network (DAN) and ventral attentionnetwork (VAN) are two networks responsible for attentional processing.The VAN is involved in involuntary actions and exhibits increasedactivity upon detection of salient targets, especially when they appearin unexpected locations (bottom-up activity, e.g. when an automobiledriver unexpectedly senses a hazard or unexpected situation). The DAN isinvolved in voluntary (top-down) orienting and increases activity afterpresentation of cues indicating where, when, or to what individualsshould direct their attention [FOX M D, Corbetta M, Snyder A Z, VincentJ L, Raichle M E. Spontaneous neuronal activity distinguishes humandorsal and ventral attention systems. Proc Natl Acad Sci USA103(2006):10046-10051; WEN X, Yao L, Liu Y, Ding M. Causal interactionsin attention networks predict behavioral performance. J Neurosci 32(4,2012):1284-1292]. The DAN is bilaterally centered in the intraparietalsulcus and the frontal eye field. The VAN is largely right lateralizedin the temporal-parietal junction and the ventral frontal cortex.

The attention systems (e.g., VAN and DAN) have been investigated longbefore their identification as resting state networks, and functionsattributed to the VAN have in the past been attributed to the locusceruleus/noradrenaline system [ASTON-JONES G, Cohen J D. An integrativetheory of locus coeruleus-norepinephrine function: adaptive gain andoptimal performance. Annu Rev Neurosci 28(2005):403-50; BOURET S, Sara SJ. Network reset: a simplified overarching theory of locus coeruleusnoradrenaline function. Trends Neurosci 28(11, 2005):574-82; SARA S J,Bouret S. Orienting and Reorienting: The Locus Coeruleus MediatesCognition through Arousal. Neuron 76(1, 2012):130-41; BERRIDGE C W,Waterhouse B D. The locus coeruleus-noradrenergic system: modulation ofbehavioral state and state-dependent cognitive processes. Brain ResBrain Res Rev 42(1, 2003):33-84].

The attention systems originally described by PETERSON and Posner aremore expansive than just the VAN and DAN system, with interactinganatomical components corresponding to alerting, orienting, andexecutive control [PETERSEN S E, Posner M I. The attention system of thehuman brain: 20 years after. Annu Rev Neurosci 35(2012):73-89]. In thatdescription, DAN and VAN comprise significant portions of the orientingsystem, and components largely involving locus ceruleus-norepinephrinefunction comprise the alerting system. Other resting state networks areinvolved with executive control [BECKMANN C F, DeLuca M, Devlin J T,Smith S M. Investigations into resting-state connectivity usingindependent component analysis. Philos Trans R Soc Lond B Biol Sci360(1457, 2005):1001-1013; JUST M A, Cherkassky V L, Keller T A, Kana RK, Minshew N J. Functional and anatomical cortical underconnectivity inautism: evidence from an FMRI study of an executive function task andcorpus callosum morphometry. Cereb Cortex 17(4, 2007):951-961].

The alerting, orienting, and executive control systems, and presumablytheir constituent resting state networks, all appear to be abnormal inautistic individuals [KEEHN B, Müller R A, Townsend J. Atypicalattentional networks and the emergence of autism. Neurosci Biobehav Rev37(2, 2013):164-183].

MENON and colleagues describe the anterior insula as being at the heartof the ventral attention system [ECKERT M A, Menon V, Walczak A,Ahlstrom J, Denslow S, Horwitz A, Dubno J R. At the heart of the ventralattention system: the right anterior insula. Hum Brain Mapp 30(8,2009):2530-2541; MENON V, Uddin L Q. Saliency, switching, attention andcontrol: a network model of insula function. Brain Struct Funct 214(5-6,2010):655-667]. However, SEELEY and colleagues used region-of-interestand independent component analyses of resting-state fMRI data todemonstrate the existence of an independent brain network comprised ofboth the anterior insula and dorsal ACC, along with subcorticalstructures including the amygdala, substantia nigra/ventral tegmentalarea, and thalamus. This network is distinct from the otherwell-characterized large-scale brain networks, e.g. the default modenetwork [SEELEY V W V, Menon V, Schatzberg A F, Keller J, Glover G H,Kenna H, et al. Dissociable intrinsic connectivity networks for salienceprocessing and executive control. J Neurosci 2007; 27(9):2349-2356].CAUDA and colleagues found that the human insula is functionallyinvolved in two distinct neural networks: i) the anterior pattern isrelated to the ventralmost anterior insula, and is connected to therostral anterior cingulate cortex, the middle and inferior frontalcortex, and the temporoparietal cortex; ii) the posterior pattern isassociated with the dorsal posterior insula, and is connected to thedorsal-posterior cingulate, sensorimotor, premotor, supplementary motor,temporal cortex, and to some occipital areas [CAUDA F, D'Agata F, SaccoK, Duca S, Geminiani G, Vercelli A. Functional connectivity of theinsula in the resting brain. Neuroimage 55(1, 2011):8-23; CAUDA F,Vercelli A. How many clusters in the insular cortex? Cereb Cortex. 2012Sep. 30. (Epub ahead of print, pp. 1-2)]. TAYLOR and colleagues alsoreport two such resting networks [TAYLOR K S, Seminowicz D A, Davis K D.Two systems of resting state connectivity between the insula andcingulate cortex. Hum Brain Mapp 30(9, 2009):2731-2745]. DEEN andcolleagues found three such resting state networks [DEEN B, Pitskel N B,Pelphrey K A. Three systems of insular functional connectivityidentified with cluster analysis. Cereb Cortex 21(7, 2011):1498-1506].

Resting state networks involving the insula, not necessarily part of theattention systems, also appear to be significantly abnormal in autisticindividuals [UDDIN L Q, Menon V. The anterior insula in autism:under-connected and under-examined. Neurosci Biobehav Rev 33(8, 2009):1198-1203; DI MARTINO A, Shehzad Z, Kelly C, Roy A K, Gee D G, Uddin LQ, Gotimer K, Klein D F, Castellanos F X, Milham M P. Relationshipbetween cingulo-insular functional connectivity and autistic traits inneurotypical adults. Am J Psychiatry 166(8, 2009):891-899]. The amygdalais prominent in some such resting state networks, and its abnormality inautistic individuals is said to contribute to autistic behavior [von demHAGEN E A, Stoyanova R S, Baron-Cohen S, Calder A J. Reduced functionalconnectivity within and between ‘social’ resting state networks inautism spectrum conditions. Soc Cogn Affect Neurosci. 2012 Jun. 8 (Epubahead of print); KLEINHANS N M, Richards T, Sterling L, Stegbauer K C,Mahurin R, Johnson L C, Greenson J, Dawson G, Aylward E. Abnormalfunctional connectivity in autism spectrum disorders during faceprocessing. Brain. 2008 April; 131(Pt 4):1000-1012; BARON-COHEN S, RingH A, Bullmore E T, Wheelwright S, Ashwin C, Williams S C. The amygdalatheory of autism. Neurosci Biobehav Rev 24(3, 2000):355-364].

Taken together, the publications cited above suggest that the defaultmode network as well as many other resting state networks may beabnormal in autistic individuals. In general, individual resting stateautistic networks may have abnormally low activity, and the autisticindividual may have difficulty deactivating one resting state network toactivate another (toggling). The difficulty in deactivation may be aresult of abnormally high local neuronal connectivity within aparticular resting state network and a lack of connectivity betweendifferent networks. As a normal individual matures, there is acharacteristic decrease in such local connectivity and an increase inlong-range connectivity [DOSENBACH N U, Nardos B, Cohen A L, et al.Prediction of individual brain maturity using fMRI. Science 329(5997,2010):1358-1361]. This maturation appears to be deficient in autisticindividuals and has in fact given rise to a functional connectivitytheory of autism [JUST M A, Keller T A, Malave V L, Kana R K, Varma S.Autism as a neural systems disorder: a theory of frontal-posteriorunderconnectivity. Neurosci Biobehav Rev 36(4, 2012):1292-1313; LEWIS JD, Elman J L. Growth-related neural reorganization and the autismphenotype: a test of the hypothesis that altered brain growth leads toaltered connectivity. Dev Sci 11(1, 2008):135-155; MULLER R A. From locito networks and back again: anomalies in the study of autism. Ann NYAcad Sci 1145(2008):300-315]. Some of the apparent localover-connectivity and long-range under-connectivity in autisticindividuals may be an artifact of movement during measurement,especially in young children who are prone to movement. However,notwithstanding possible exaggeration of the connection abnormalitieswhen the data are not properly scrubbed for head movement, theconnectivity theory may serve as the basis of interventions involvingvagus nerve stimulation as now described [MULLER R A, Shih P, Keehn B,Deyoe J R, Leyden K M, Shukla D K. Underconnected, but how? A survey offunctional connectivity MRI studies in autism spectrum disorders. CerebCortex 21(10, 2011):2233-2243; Van DIJK K R, Sabuncu M R, Buckner R L.The influence of head motion on intrinsic functional connectivity MRI.Neuroimage 59(1, 2012):431-438; POWER J D, Barnes K A, Snyder A Z,Schlaggar B L, Petersen S E. Spurious but systematic correlations infunctional connectivity MRI networks arise from subject motion.Neuroimage 59(3, 2012):2142-2154; SATTERTHWAITE T D, Wolf D H, LougheadJ, Ruparel K, Elliott M A, Hakonarson H, Gur R C, Gur R E. Impact ofin-scanner head motion on multiple measures of functional connectivity:relevance for studies of neurodevelopment in youth. Neuroimage 60(1,2012):623-632].

Before disclosing methods for modulating resting state networks usingvagal nerve stimulation, we first describe how stimulation of the vagusnerve can affect some of the most relevant components of the brain, suchas the insula and amygdala (see FIG. 1 ). These structures are involvedin the higher-level processing of sensory information, and thatprocessing is often abnormal in autistic individuals. The sensoryinformation consists not only of hearing, vision, taste & smell, andtouch, but also other sensory modalities such as proprioception,nociception and interoception, and the problem that the autisticindividuals experience is often not with the sensation per se, but withthe integration of different sensory modalities and the association ofsensory experience with affective and empathic processes. In otherwords, the autistic individual may not recognize that a sensation issalient, which a normal individual would act upon [MARCO E J, Hinkley LB, Hill S S, Nagarajan S S. Sensory processing in autism: a review ofneurophysiologic findings. Pediatr Res 69(5 Pt 2, 2011):48R-54R; SEELEYV W V, Menon V, Schatzberg A F, Keller J, Glover G H, Kenna H, Reiss AL, Greicius M D. Dissociable intrinsic connectivity networks forsalience processing and executive control. J Neurosci 27(9,2007):2349-2356; UDDIN L Q, Menon V. The anterior insula in autism:under-connected and under-examined. Neurosci Biobehav Rev 33(8,2009):1198-1203].

For purposes of illustration in FIG. 1 , we use interoceptive neuralpathways leading to the insula and amygdala (which are involved in thesensation of temperature, itch, and the like), because they have aninherent association with emotion [CRAIG A D. How do you feel—now? Theanterior insula and human awareness. Nat Rev Neurosci 10(1,2009):59-70]. These pathways are said to be abnormal in autisticindividuals [EBISCH S J, Gallese V, Wllems R M, Mantini D, Groen W B,Romani G L, Buitelaar J K, Bekkering H. Altered intrinsic functionalconnectivity of anterior and posterior insula regions inhigh-functioning participants with autism spectrum disorder. Hum BrainMapp 32(7, 2011):1013-1028]. Anatomically, interoceptive sensations aredistinguished from surface touch (tactile) sensations by theirassociation with the spinothalamic projection that ascend in thecontralateral spinal cord, rather than with the dorsal column/mediallemniscal system which ascends the ipsilateral spinal cord. However,both contralateral and ipsilateral circuits are shown in the spinal cordin FIG. 1 to indicate that the discussion applies more generally tosensory processing, not just the interoception that is used for purposesof discussion.

Many neural circuits that are involved in interoception are located inhigher regions of the central nervous system, but the invention cannevertheless electrically stimulate the vagus nerve in such a way as tomodulate the activity of those neural circuits. They are shown in ofFIG. 1 and described in paragraphs that follow [CRAIG A D. How do youfeel? Interoception: the sense of the physiological condition of thebody. Nat Rev Neurosci 3(8, 2002):655-666; BIELEFELDT K, Christianson JA, Davis B M. Basic and clinical aspects of visceral sensation:transmission in the CNS. Neurogastroenterol Motil 17(4, 2005):488-499;MAYER E A, Naliboff B D, Craig A D. Neuroimaging of the brain-gut axis:from basic understanding to treatment of functional GI disorders.Gastroenterology 131(6, 2006):1925-1942].

Interoceptive sensations arise from signals sent by parasympathetic andsympathetic afferent nerves. The latter are considered to be the primaryculprit for pain and other unpleasant emotional feelings, butparasympathetic afferents also contribute. Among afferents whose cellbodies are found in the dorsal root ganglia, the ones having type B cellbodies are most significant, which terminate in lamina I of the spinaland trigeminal dorsal horns. Other afferent nerves that terminate in thedeep dorsal horn provide signals related to mechanoreceptive,proprioceptive and nociceptive activity.

Lamina I neurons project to many locations. First, they project to thesympathetic regions in the intermediomedial and intermediolateral cellcolumns of the thoracolumbar cord, where the sympathetic preganglioniccells of the autonomic nervous system originate (See FIG. 1 ). Second,in the medulla, lamina I neurons project to the AI catecholaminergiccell groups of the ventrolateral medulla and then to sites in therostral ventrolateral medulla (RVLM) which is interconnected with thesympathetic neurons that project to spinal levels. Only a limited numberof discrete regions within the supraspinal central nervous systemproject to sympathetic preganglionic neurons in the intermediolateralcolumn (see FIG. 1 ). The most important of these regions are therostral ventral lateral medulla (RVLM), the rostral ventromedial medulla(RVMM), the midline raphe, the paraventricular nucleus (PVN) of thehypothalamus, the medullocervical caudal pressor area (mCPA), and the A5cell group of the pons. The first four of these connections to theintermediolateral nucleus are shown in FIG. 1 [STRACK A M, Sawyer W B,Hughes J H, Platt K B, Loewy A D. A general pattern of CNS innervationof the sympathetic outflow demonstrated by transneuronal pseudorabiesviral infections. Brain Res. 491(1, 1989): 156-162].

The rostral ventral lateral medulla (RVLM) is the primary regulator ofthe sympathetic nervous system, sending excitatory fibers(glutamatergic) to the sympathetic preganglionic neurons located in theintermediolateral nucleus of the spinal cord. Vagal afferents synapse inthe NTS, and their projections reach the RVLM via the caudalventrolateral medulla. However, resting sympathetic tone also comes fromsources above the pons, from hypothalamic nuclei, various hindbrain andmidbrain structures, as well as the forebrain and cerebellum, whichsynapse in the RVLM. Only the hypothalamic projection to the RVLM isshown in FIG. 1 . The RVLM shares its role as a primary regulator of thesympathetic nervous system with the rostral ventromedial medulla (RVMM)and medullary raphe. Differences in function between the RVLM versusRVMM/medullary raphe have been elucidated for cardiovascular control,but are not well characterized for gastrointestinal control.Differential control of the RVLM by the hypothalamus may also occur viacirculating hormones such as vasopressin. The RVMM contains at leastthree populations of nitric oxide synthase neurons that send axons toinnervate functionally similar sites in the NTS and nucleus ambiguus.Circuits connecting the RVMM and RVLM may be secondary, via the NTS andhypothalamus.

In the medulla, lamina I neurons also project another site, namely, tothe A2 cell group of the nucleus of the solitary tract, which alsoreceives direct parasympathetic (vagal and glossopharyngeal) afferentinput. As indicated above, the nucleus of the solitary tract projects tomany locations, including the parabrachial nucleus. In the pons andmesencephalon, lamina I neurons project to the periaqueductal grey(PAG), the main homeostatic brainstem motor site, and to theparabrachial nucleus. Sympathetic and parasympathetic afferent activityis integrated in the parabrachial nucleus. It in turn projects to theinsular cortex by way of the ventromedial thalamic nucleus (VMb, alsoknown as VPMpc). A direct projection from lamina I to the ventromedialnucleus (VMpo), and a direct projection from the nucleus tractussolitarius to the VMb, provide a rostrocaudally contiguous column thatrepresents all contralateral homeostatic afferent input. They projecttopographically to the mid/posterior dorsal insula (See FIG. 1 ).

In humans, this cortical image is re-represented in the anterior insulaon the same side of the brain. The parasympathetic activity isre-represented in the left (dominant) hemisphere, whereas thesympathetic activity is re-represented in the right (non-dominant)hemisphere. These re-representations provide the foundation for asubjective evaluation of interoceptive state, which is forwarded to theorbitofrontal cortex (See FIG. 1 ).

The right anterior insula is associated with subjective awareness ofhomeostatic emotions (e.g., visceral and somatic pain, temperature,sexual arousal, hunger, and thirst) as well as all emotions (e.g.,anger, fear, disgust, sadness, happiness, trust, love, empathy, socialexclusion). This region is intimately interconnected with the anteriorcingulate cortex (ACC). Unpleasant sensations are directly correlatedwith ACC activation. The anterior cingulate cortex and insula are bothstrongly interconnected with the orbitofrontal cortex, amygdala,hypothalamus, and brainstem homeostatic regions, of which only a fewconnections are shown in FIG. 1 .

Methods of the present invention comprise modulation of two targetregions using vagus nerve stimulation. A first method directly targetsthe front end of the interoceptive pathways shown in FIG. 1 (nucleustractus solitarius, area postrema, and dorsal motor nucleus). The secondmethod targets the distal end of the interoceptive pathways (anteriorinsula and anterior cingulate cortex) and is the one associated withmodulating the resting state networks that were summarized above.

According to the first method, electrical stimulation of A and B fibersalone of a vagus nerve causes increased inhibitory neurotransmitters inthe brainstem, which in turn inhibits signals sent to the parabrachialnucleus, VMb and VMpo. The stimulation uses special devices and aspecial waveform (described below), which minimize effects involving Cfibers that might produce unwanted side-effects. The electricalstimulation first affects the dorsal vagal complex, which is the majortermination site of vagal afferent nerve fibers. The dorsal vagalcomplex consists of the area postrema (AP), the nucleus of the solitarytract (NTS) and the dorsal motor nucleus of the vagus. The AP projectsto the NTS and dorsal motor nucleus of the vagus bilaterally. It alsoprojects bilaterally to the parabrachial nucleus and receives directafferent input from the vagus nerve. Thus, the area postrema is in aunique position to receive and modulate ascending interoceptiveinformation and to influence autonomic outflow [PRICE C J, Hoyda T D,Ferguson A V. The area postrema: a brain monitor and integrator ofsystemic autonomic state. Neuroscientist 14(2, 2008):182-194].

Projections to and from the locus ceruleus are particularly significantin the present invention because they are also used in the second methodthat is described below. The vagus nerve transmits information to thelocus ceruleus via the nucleus tractus solitarius (NTS), which has adirect projection to the dendritic region of the locus ceruleus. Otherafferents to, and efferents from, the locus ceruleus are described bySARA et al, SAMUELS et al, and ASTON-JONES [SARA S J, Bouret S.Orienting and Reorienting: The Locus Coeruleus Mediates Cognitionthrough Arousal. Neuron 76(1, 2012):130-41; SAMUELS E R, Szabadi E.Functional neuroanatomy of the noradrenergic locus coeruleus: its rolesin the regulation of arousal and autonomic function part I: principlesof functional organisation. Curr Neuropharmacol 6(3):235-53; SAMUELS, E.R., and Szabadi, E. Functional neuroanatomy of the noradrenergic locuscoeruleus: its roles in the regulation of arousal and autonomic functionpart II: physiological and pharmacological manipulations andpathological alterations of locus coeruleus activity in humans. Curr.Neuropharmacol. 6(2008), 254-285; Gary ASTON-JONES. Norepinephrine.Chapter 4 (pp. 47-57) in: Neuropsychopharmacology: The Fifth Generationof Progress (Kenneth L. Davis, Dennis Charney, Joseph T. Coyle, CharlesNemeroff, eds.) Philadelphia: Lippincott Williams & Wilkins, 2002].

In addition to the NTS, the locus ceruleus receives input from thenucleus gigantocellularis and its neighboring nucleusparagigantocellularis, the prepositus hypoglossal nucleus, theparaventricular nucleus of the hypothalamus, Barrington's nucleus, thecentral nucleus of the amygdala, and prefrontal areas of the cortex.These same nuclei receive input from the NTS, such that stimulation ofthe vagus nerve may modulate the locus ceruleus via the NTS and asubsequent relay through these structures.

The locus ceruleus has widespread projections throughout the cortex[SAMUELS E R, Szabadi E. Functional neuroanatomy of the noradrenergiclocus coeruleus: its roles in the regulation of arousal and autonomicfunction part I: principles of functional organisation. CurrNeuropharmacol 6 (3):235-53]. It also projects to subcortical regions,notably the raphe nuclei, which release serotonin to the rest of thebrain. An increased dorsal raphe nucleus firing rate is thought to besecondary to an initial increased locus ceruleus firing rate from vagusnerve stimulation [Adrienne E. DORR and Guy Debonnelv. Effect of vagusnerve stimulation on serotonergic and noradrenergic transmission. JPharmacol Exp Ther 318(2, 2006):890-898; MANTA S, Dong J, Debonnel G,Blier P. Enhancement of the function of rat serotonin and norepinephrineneurons by sustained vagus nerve stimulation. J Psychiatry Neurosci34(4, 2009):272-80]. The locus ceruleus also has projections toautonomic nuclei, including the dorsal motor nucleus of the vagus, asshown in FIG. 1 [FUKUDA, A., Minami, T., Nabekura, J., Oomura, Y. Theeffects of noradrenaline on neurones in the rat dorsal motor nucleus ofthe vagus, in vitro. J. Physiol., 393 (1987): 213-231; MARTINEZ-PENA yValenzuela, I., Rogers, R. C., Hermann, G. E., Travagli, R. A. (2004)Norepinephrine effects on identified neurons of the rat dorsal motornucleus of the vagus. Am. J. Physiol. Gas-trointest. Liver Physiol.,286,G333-G339; TERHORST, G. J., Toes, G. J., Van Wlligen, J. D. Locuscoeruleus projections to the dorsal motor vagus nucleus in the rat.Neuroscience,45(1991): 153-160].

The present invention modulates the activity of resting state networksvia the locus ceruleus (or alternatively via another structure that haswidespread projections), by electrically stimulating a vagus nerve.Stimulation of a network via the locus ceruleus may activate ordeactivate a network, depending on the detailed configuration ofadrenergic receptor subtypes within the network and their roles inenhancing or depressing neural activity within the network, as well assubsequent network-to-network interactions. It is presumed that theindividual has already been evaluated so as to assess abnormality in hisresting state networks. According to the invention, one key topreferential stimulation of a particular resting state network, such asthe DMN or those involving the insula and ACC, is to use a vagus nervestimulation signal that entrains to the signature EEG pattern of thatnetwork (see below and MANTINI D, Perrucci M G, Del Gratta C, Romani GL, Corbetta M. Electrophysiological signatures of resting state networksin the human brain. Proc Natl Acad Sci USA 104(32, 2007):13170-13175).By this EEG entrainment method, it may be possible to preferentiallyattenuate or deactivate, for example, the insula/ACC networks in anautistic patient. Activation of another network such as the VAN or DMNmay also produce the same effect, via network-to-network interactions.Although the locus ceruleus is presumed to project to all of the restingnetworks, it is thought to project most strongly to the ventralattention network (VAN) [CORBETTA M, Patel G, Shulman G L. Thereorienting system of the human brain: from environment to theory ofmind. Neuron 58(3, 2008):306-24; MANTINI D, Corbetta M, Perrucci M G,Romani G L, Del Gratta C. Large-scale brain networks account forsustained and transient activity during target detection. Neuroimage44(1, 2009):265-274]. Thus, deactivation of a particular network mayalso be attempted by activating another resting state network, becausethe brain switches between them. According to the invention, theactivation or deactivation of a resting state network may be undertakenin a particular behavioral situation by stimulation of the vagus nervewhenever the activation or deactivation would be considered normal inthe then-present behavioral context.

Description of the Magnetic and Electrode-Based NerveStimulating/Modulating Devices

Devices of the invention that are used to stimulate a vagus nerve willnow be described. Either a magnetic stimulation device or anelectrode-based device may be used for that purpose. FIG. 2A is aschematic diagram of Applicant's magnetic nerve stimulating/modulatingdevice 301 for delivering impulses of energy to nerves for the treatmentof medical conditions such as autism spectrum disorders. As shown,device 301 may include an impulse generator 310; a power source 320coupled to the impulse generator 310; a control unit 330 incommunication with the impulse generator 310 and coupled to the powersource 320; and a magnetic stimulator coil 341 coupled via wires toimpulse generator coil 310. The stimulator coil 341 is toroidal inshape, due to its winding around a toroid of core material.

Although the magnetic stimulator coil 341 is shown in FIG. 2A to be asingle coil, in practice the coil may also comprise two or more distinctcoils, each of which is connected in series or in parallel to theimpulse generator 310. Thus, the coil 341 that is shown in FIG. 2Arepresents all the magnetic stimulator coils of the device collectively.In a preferred embodiment that is discussed below, coil 341 actuallycontains two coils that may be connected either in series or in parallelto the impulse generator 310.

The item labeled in FIG. 2A as 351 is a volume, surrounding the coil341, that is filled with electrically conducting medium. As shown, themedium not only encloses the magnetic stimulator coil, but is alsodeformable such that it is form-fitting when applied to the surface ofthe body. Thus, the sinuousness or curvature shown at the outer surfaceof the electrically conducting medium 351 corresponds also tosinuousness or curvature on the surface of the body, against which theconducting medium 351 is applied, so as to make the medium and bodysurface contiguous. As time-varying electrical current is passed throughthe coil 341, a magnetic field is produced, but because the coil windingis toroidal, the magnetic field is spatially restricted to the interiorof the toroid. An electric field and eddy currents are also produced.The electric field extends beyond the toroidal space and into thepatient's body, causing electrical currents and stimulation within thepatient. The volume 351 is electrically connected to the patient at atarget skin surface in order to significantly reduce the current passedthrough the coil 341 that is needed to accomplish stimulation of thepatient's nerve or tissue. In a preferred embodiment of the magneticstimulator that is discussed below, the conducting medium with which thecoil 341 is in contact need not completely surround the toroid.

The design of the magnetic stimulator 301, which is also adapted hereinfor use with surface electrodes, makes it possible to shape the electricfield that is used to selectively stimulate a relatively deep nerve suchas a vagus nerve in the patient's neck. Furthermore, the design producessignificantly less pain or discomfort (if any) to a patient, at the siteof stimulation on the skin, than stimulator devices that are currentlyknown in the art. Conversely, for a given amount of pain or discomforton the part of the patient (e.g., the threshold at which such discomfortor pain begins), the design achieves a greater depth of penetration ofthe stimulus under the skin.

An alternate embodiment of the present invention is shown in FIG. 2B,which is a schematic diagram of an electrode-based nervestimulating/modulating device 302 for delivering impulses of energy tonerves for the treatment of medical conditions. As shown, device 302 mayinclude an impulse generator 310; a power source 320 coupled to theimpulse generator 310; a control unit 330 in communication with theimpulse generator 310 and coupled to the power source 320; andelectrodes 340 coupled via wires 345 to impulse generator 310. In apreferred embodiment, the same impulse generator 310, power source 320,and control unit 330 may be used for either the magnetic stimulator 301or the electrode-based stimulator 302, allowing the user to changeparameter settings depending on whether coils 341 or the electrodes 340are attached.

Although a pair of electrodes 340 is shown in FIG. 2B, in practice theelectrodes may also comprise three or more distinct electrode elements,each of which is connected in series or in parallel to the impulsegenerator 310. Thus, the electrodes 340 that are shown in FIG. 2Brepresent all electrodes of the device collectively.

The item labeled in FIG. 2B as 350 is a volume, contiguous with anelectrode 340, that is filled with electrically conducting medium. Asdescribed below in connection with particular embodiments of theinvention, conducting medium in which the electrode 340 is embedded neednot completely surround an electrode. As also described below inconnection with a preferred embodiment, the volume 350 is electricallyconnected to the patient at a target skin surface in order to shape thecurrent density passed through an electrode 340 that is needed toaccomplish stimulation of the patient's nerve or tissue. The electricalconnection to the patient's skin surface is through an interface 351. Inone embodiment, the interface is made of an electrically insulating(dielectric) material, such as a thin sheet of Mylar. In that case,electrical coupling of the stimulator to the patient is capacitive. Inother embodiments, the interface comprises electrically conductingmaterial, such as the electrically conducting medium 350 itself, or anelectrically conducting or permeable membrane. In that case, electricalcoupling of the stimulator to the patient is ohmic. As shown, theinterface may be deformable such that it is form-fitting when applied tothe surface of the body. Thus, the sinuousness or curvature shown at theouter surface of the interface 351 corresponds also to sinuousness orcurvature on the surface of the body, against which the interface 351 isapplied, so as to make the interface and body surface contiguous.

The control unit 330 controls the impulse generator 310 to generate asignal for each of the device's coils or electrodes. The signals areselected to be suitable for amelioration of a particular medicalcondition, when the signals are applied non-invasively to a target nerveor tissue via the coil 341 or electrodes 340. It is noted that nervestimulating/modulating device 301 or 302 may be referred to by itsfunction as a pulse generator. Patent application publicationsUS2005/0075701 and US2005/0075702, both to SHAFER, contain descriptionsof pulse generators that may be applicable to the present invention. Byway of example, a pulse generator is also commercially available, suchas Agilent 33522A Function/Arbitrary Waveform Generator, AgilentTechnologies, Inc., 5301 Stevens Creek Blvd Santa Clara Calif. 95051.

The control unit 330 may also comprise a general purpose computer,comprising one or more CPU, computer memories for the storage ofexecutable computer programs (including the system's operating system)and the storage and retrieval of data, disk storage devices,communication devices (such as serial and USB ports) for acceptingexternal signals from the system's keyboard, computer mouse, andtouchscreen, as well as any externally supplied physiological signals(see FIG. 8 ), analog-to-digital converters for digitizing externallysupplied analog signals (see FIG. 8 ), communication devices for thetransmission and receipt of data to and from external devices such asprinters and modems that comprise part of the system, hardware forgenerating the display of information on monitors that comprise part ofthe system, and busses to interconnect the above-mentioned components.Thus, the user may operate the system by typing instructions for thecontrol unit 330 at a device such as a keyboard and view the results ona device such as the system's computer monitor, or direct the results toa printer, modem, and/or storage disk. Control of the system may bebased upon feedback measured from externally supplied physiological orenvironmental signals. Alternatively, the control unit 330 may have acompact and simple structure, for example, wherein the user may operatethe system using only an on/off switch and power control wheel or knob.

Parameters for the nerve or tissue stimulation include power level,frequency and train duration (or pulse number). The stimulationcharacteristics of each pulse, such as depth of penetration, strengthand selectivity, depend on the rise time and peak electrical energytransferred to the electrodes or coils, as well as the spatialdistribution of the electric field that is produced by the electrodes orcoils. The rise time and peak energy are governed by the electricalcharacteristics of the stimulator and electrodes or coils, as well as bythe anatomy of the region of current flow within the patient. In oneembodiment of the invention, pulse parameters are set in such as way asto account for the detailed anatomy surrounding the nerve that is beingstimulated [Bartosz SAWICKI, Robert Szmurło, Przemysław Płonecki, JacekStarzyński, Stanisław Wincenciak, Andrzej Rysz. Mathematical Modellingof Vagus Nerve Stimulation. pp. 92-97 in: Krawczyk, A. ElectromagneticField, Health and Environment: Proceedings of EHE'07. Amsterdam, 105Press, 2008]. Pulses may be monophasic, biphasic or polyphasic.Embodiments of the invention include those that are fixed frequency,where each pulse in a train has the same inter-stimulus interval, andthose that have modulated frequency, where the intervals between eachpulse in a train can be varied.

FIG. 2C illustrates an exemplary electrical voltage/current profile fora stimulating, blocking and/or modulating impulse applied to a portionor portions of selected nerves in accordance with an embodiment of thepresent invention. For the preferred embodiment, the voltage and currentrefer to those that are non-invasively produced within the patient bythe stimulator coils or electrodes. As shown, a suitable electricalvoltage/current profile 400 for the blocking and/or modulating impulse410 to the portion or portions of a nerve may be achieved using pulsegenerator 310. In a preferred embodiment, the pulse generator 310 may beimplemented using a power source 320 and a control unit 330 having, forinstance, a processor, a clock, a memory, etc., to produce a pulse train420 to the coil 341 or electrodes 340 that deliver the stimulating,blocking and/or modulating impulse 410 to the nerve. Nervestimulating/modulating device 301 or 302 may be externally poweredand/or recharged or may have its own power source 320. The parameters ofthe modulation signal 400, such as the frequency, amplitude, duty cycle,pulse width, pulse shape, etc., are preferably programmable. An externalcommunication device may modify the pulse generator programming toimprove treatment.

In addition, or as an alternative to the devices to implement themodulation unit for producing the electrical voltage/current profile ofthe stimulating, blocking and/or modulating impulse to the electrodes orcoils, the device disclosed in patent publication No. US2005/0216062 maybe employed. That patent publication discloses a multifunctionalelectrical stimulation (ES) system adapted to yield output signals foreffecting electromagnetic or other forms of electrical stimulation for abroad spectrum of different biological and biomedical applications,which produce an electric field pulse in order to non-invasivelystimulate nerves. The system includes an ES signal stage having aselector coupled to a plurality of different signal generators, eachproducing a signal having a distinct shape, such as a sine wave, asquare or a saw-tooth wave, or simple or complex pulse, the parametersof which are adjustable in regard to amplitude, duration, repetitionrate and other variables. Examples of the signals that may be generatedby such a system are described in a publication by LIBOFF [A. R. LIBOFF.Signal shapes in electromagnetic therapies: a primer. pp. 17-37 in:Bioelectromagnetic Medicine (Paul J. Rosch and Marko S. Markov, eds.).New York: Marcel Dekker (2004)]. The signal from the selected generatorin the ES stage is fed to at least one output stage where it isprocessed to produce a high or low voltage or current output of adesired polarity whereby the output stage is capable of yielding anelectrical stimulation signal appropriate for its intended application.Also included in the system is a measuring stage which measures anddisplays the electrical stimulation signal operating on the substancebeing treated, as well as the outputs of various sensors which senseprevailing conditions prevailing in this substance, whereby the user ofthe system can manually adjust the signal, or have it automaticallyadjusted by feedback, to provide an electrical stimulation signal ofwhatever type the user wishes, who can then observe the effect of thissignal on a substance being treated.

The stimulating and/or modulating impulse signal 410 preferably has afrequency, an amplitude, a duty cycle, a pulse width, a pulse shape,etc. selected to influence the therapeutic result, namely, stimulatingand/or modulating some or all of the transmission of the selected nerve.For example, the frequency may be about 1 Hz or greater, such as betweenabout 15 Hz to 100 Hz, preferably between about 15-50 Hz and morepreferably between about 15-35 Hz. In an exemplary embodiment, thefrequency is 25 Hz. The modulation signal may have a pulse widthselected to influence the therapeutic result, such as about 1microseconds to about 1000 microseconds, preferably about 100-400microseconds and more preferably about 200-400 microseconds. Forexample, the electric field induced or produced by the device withintissue in the vicinity of a nerve may be about 5 to 600 V/m, preferablyless than 100 V/m, and even more preferably less than 30 V/m. Thegradient of the electric field may be greater than 2 V/m/mm. Moregenerally, the stimulation device produces an electric field in thevicinity of the nerve that is sufficient to cause the nerve todepolarize and reach a threshold for action potential propagation, whichis approximately 8 V/m at 1000 Hz. The modulation signal may have a peakvoltage amplitude selected to influence the therapeutic result, such asabout 0.2 volts or greater, such as about 0.2 volts to about 40 volts,preferably between about 1-20 volts and more preferably between about2-12 volts.

An objective of the disclosed stimulators is to provide both nerve fiberselectivity and spatial selectivity. Spatial selectivity may be achievedin part through the design of the electrode or coil configuration, andnerve fiber selectivity may be achieved in part through the design ofthe stimulus waveform, but designs for the two types of selectivity areintertwined. This is because, for example, a waveform may selectivelystimulate only one of two nerves whether they lie close to one anotheror not, obviating the need to focus the stimulating signal onto only oneof the nerves [GRILL W and Mortimer J T. Stimulus waveforms forselective neural stimulation. IEEE Eng. Med. Biol. 14 (1995): 375-385].These methods complement others that are used to achieve selective nervestimulation, such as the use of local anesthetic, application ofpressure, inducement of ischemia, cooling, use of ultrasound, gradedincreases in stimulus intensity, exploiting the absolute refractoryperiod of axons, and the application of stimulus blocks [John E. SWETTand Charles M. Bourassa. Electrical stimulation of peripheral nerve. In:Electrical Stimulation Research Techniques, Michael M. Patterson andRaymond P. Kesner, eds. Academic Press. (New York, 1981) pp. 243-295].

To date, the selection of stimulation waveform parameters for nervestimulation has been highly empirical, in which the parameters arevaried about some initially successful set of parameters, in an effortto find an improved set of parameters for each patient. A more efficientapproach to selecting stimulation parameters might be to select astimulation waveform that mimics electrical activity in the anatomicalregions that one is attempting stimulate indirectly, in an effort toentrain the naturally occurring electrical waveform, as suggested inU.S. Pat. No. 6,234,953, entitled Electrotherapy device using lowfrequency magnetic pulses, to THOMAS et al. and application numberUS20090299435, entitled Systems and methods for enhancing or affectingneural stimulation efficiency and/or efficacy, to GLINER et al. One mayalso vary stimulation parameters iteratively, in search of an optimalsetting [U.S. Pat. No. 7,869,885, entitled Threshold optimization fortissue stimulation therapy, to BEGNAUD et al]. However, some stimulationwaveforms, such as those described herein, are discovered by trial anderror, and then deliberately improved upon.

Invasive nerve stimulation typically uses square wave pulse signals.However, Applicant found that square waveforms are not ideal fornon-invasive stimulation as they produce excessive pain. Prepulses andsimilar waveform modifications have been suggested as methods to improveselectivity of nerve stimulation waveforms, but Applicant did not findthem ideal [Aleksandra VUCKOVIC, Marco Tosato and Johannes J Struijk. Acomparative study of three techniques for diameter selective fiberactivation in the vagal nerve: anodal block, depolarizing prepulses andslowly rising pulses. J. Neural Eng. 5 (2008): 275-286; AleksandraVUCKOVIC, Nico J. M. Rijkhoff, and Johannes J. Struijk. Different PulseShapes to Obtain Small Fiber Selective Activation by Anodal Blocking—ASimulation Study. IEEE Transactions on Biomedical Engineering 51(5,2004):698-706; Kristian HENNINGS. Selective Electrical Stimulation ofPeripheral Nerve Fibers: Accommodation Based Methods. Ph.D. Thesis,Center for Sensory-Motor Interaction, Aalborg University, Aalborg,Denmark, 2004].

Applicant also found that stimulation waveforms consisting of bursts ofsquare pulses are not ideal for non-invasive stimulation [M. I. JOHNSON,C. H. Ashton, D. R. Bousfield and J. W. Thompson. Analgesic effects ofdifferent pulse patterns of transcutaneous electrical nerve stimulationon cold-induced pain in normal subjects. Journal of PsychosomaticResearch 35 (2/3, 1991):313-321; U.S. Pat. No. 7,734,340, entitledStimulation design for neuromodulation, to De Ridder]. However, burstsof sinusoidal pulses are a preferred stimulation waveform, as shown inFIGS. 2D and 2E. As seen there, individual sinusoidal pulses have aperiod of □, and a burst consists of N such pulses. This is followed bya period with no signal (the inter-burst period). The pattern of a burstfollowed by silent inter-burst period repeats itself with a period of T.For example, the sinusoidal period □ may be between about 50-1000microseconds (equivalent to about 1-20 KHz), preferably between about100-400 microseconds (equivalent to about 2.5-10 KHz), more preferablyabout 133-400 microseconds (equivalent to about 2.5-7.5 KHZ) and evenmore preferably about 200 microseconds (equivalent to about 5 KHz); thenumber of pulses per burst may be N=1-20, preferably about 2-10 and morepreferably about 5; and the whole pattern of burst followed by silentinter-burst period may have a period T comparable to about 10-100 Hz,preferably about 15-50 Hz, more preferably about 25-35 Hz and even morepreferably about 25 Hz (a much smaller value of T is shown in FIG. 2E tomake the bursts discernable). When these exemplary values are used for Tand □, the waveform contains significant Fourier components at higherfrequencies (1/200 microseconds=5000/sec), as compared with thosecontained in transcutaneous nerve stimulation waveforms, as currentlypracticed.

Applicant is unaware of such a waveform having been used with vagusnerve stimulation, but a similar waveform has been used to stimulatemuscle as a means of increasing muscle strength in elite athletes.However, for the muscle strengthening application, the currents used(200 mA) may be very painful and two orders of magnitude larger thanwhat are disclosed herein. Furthermore, the signal used for musclestrengthening may be other than sinusoidal (e.g., triangular), and theparameters □, N, and T may also be dissimilar from the valuesexemplified above [A. DELITTO, M. Brown, M. J. Strube, S. J. Rose, andR. C. Lehman. Electrical stimulation of the quadriceps femoris in anelite weight lifter: a single subject experiment. Int J Sports Med10(1989):187-191; Alex R WARD, Nataliya Shkuratova. Russian ElectricalStimulation: The Early Experiments. Physical Therapy 82 (10, 2002):1019-1030; Yocheved LAUFER and Michal Elboim. Effect of Burst Frequencyand Duration of Kilohertz-Frequency Alternating Currents and ofLow-Frequency Pulsed Currents on Strength of Contraction, MuscleFatigue, and Perceived Discomfort. Physical Therapy 88 (10,2008):1167-1176; Alex R WARD. Electrical Stimulation UsingKilohertz-Frequency Alternating Current. Physical Therapy 89 (2,2009):181-190; J. PETROFSKY, M. Laymon, M. Prowse, S. Gunda, and J.Batt. The transfer of current through skin and muscle during electricalstimulation with sine, square, Russian and interferential waveforms.Journal of Medical Engineering and Technology 33 (2, 2009): 170-181;U.S. Pat. No. 4,177,819, entitled Muscle stimulating apparatus, toKOFSKY et al]. Burst stimulation has also been disclosed in connectionwith implantable pulse generators, but wherein the bursting ischaracteristic of the neuronal firing pattern itself [U.S. Pat. No.7,734,340 to D E RIDDER, entitled Stimulation design forneuromodulation; application US20110184486 to D E RIDDER, entitledCombination of tonic and burst stimulations to treat neurologicaldisorders]. By way of example, the electric field shown in FIGS. 2D and2E may have an Emax value of 17 V/m, which is sufficient to stimulatethe nerve but is significantly lower than the threshold needed tostimulate surrounding muscle.

High frequency electrical stimulation is also known in the treatment ofback pain at the spine [Patent application US20120197369, entitledSelective high frequency spinal cord modulation for inhibiting pain withreduced side effects and associated systems and methods, to ALATARIS etal.; Adrian A L KAISY, Iris Smet, and Jean-Pierre Van Buyten. Analgeiaof axial low back pain with novel spinal neuromodulation. Posterpresentation #202 at the 2011 meeting of The American Academy of PainMedicine, held in National Harbor, Md., Mar. 24-27, 2011]. Those methodsinvolve high-frequency modulation in the range of from about 1.5 KHz toabout 50 KHz, which is applied to the patient's spinal cord region.However, such methods are different from the present invention because,for example, they is invasive; they do not involve a bursting waveform,as in the present invention; they necessarily involve A-delta and Cnerve fibers and the pain that those fibers produce, whereas the presentinvention does not; they may involve a conduction block applied at thedorsal root level, whereas the present invention may stimulate actionpotentials without blocking of such action potentials; and/or theyinvolve an increased ability of high frequency modulation to penetratethrough the cerebral spinal fluid, which is not relevant to the presentinvention. In fact, a likely explanation for the reduced back pain thatis produced by their use of frequencies from 10 to 50 KHz is that theapplied electrical stimulus at those frequencies causes permanent damageto the pain-causing nerves, whereas the present invention involves onlyreversible effects [LEE R C, Zhang D, Hannig J. Biophysical injurymechanisms in electrical shock trauma. Annu Rev Biomed Eng2(2000):477-509].

Consider now which nerve fibers may be stimulated by the non-invasivevagus nerve stimulation. The waveform disclosed in FIG. 2 containssignificant Fourier components at high frequencies (e.g., 1/200microseconds=5000/sec), even if the waveform also has components atlower frequencies (e.g., 25/sec). Transcutaneously, A-beta, A-delta, andC fibers are typically excited at 2000 Hz, 250 Hz, and 5 Hz,respectively, i.e., the 2000 Hz stimulus is described as being specificfor measuring the response of A-beta fibers, the 250 Hz for A-deltafibers, and the 5 Hz for type C fibers [George D. BAQUIS et al.TECHNOLOGY REVIEW: THE NEUROMETER CURRENT PERCEPTION THRESHOLD (CPT).Muscle Nerve 22(Supplement 8, 1999): S247-S259]. Therefore, the highfrequency component of the noninvasive stimulation waveform willpreferentially stimulate the A-alpha and A-beta fibers, and the C fiberswill be largely unstimulated.

However, the threshold for activation of fiber types also depends on theamplitude of the stimulation, and for a given stimulation frequency, thethreshold increases as the fiber size decreases. The threshold forgenerating an action potential in nerve fibers that are impaled withelectrodes is traditionally described by Lapicque or Weiss equations,which describe how together the width and amplitude of stimulus pulsesdetermine the threshold, along with parameters that characterize thefiber (the chronaxy and rheobase). For nerve fibers that are stimulatedby electric fields that are applied externally to the fiber, as is thecase here, characterizing the threshold as a function of pulse amplitudeand frequency is more complicated, which ordinarily involves thenumerical solution of model differential equations or a case-by-caseexperimental evaluation [David BOINAGROV, Jim Loudin and DanielPalanker. Strength-Duration Relationship for Extracellular NeuralStimulation: Numerical and Analytical Models. J Neurophysiol104(2010):2236-2248].

For example, REILLY describes a model (the spatially extended nonlinearnodal model or SENN model) that may be used to calculate minimumstimulus thresholds for nerve fibers having different diameters [J.Patrick REILLY. Electrical models for neural excitation studies. JohnsHopkins A P L Technical Digest 9(1, 1988): 44-59]. According to REILLY'sanalysis, the minimum threshold for excitation of myelinated A fibers is6.2 V/m for a 20 □m diameter fiber, 12.3 V/m for a 10 □m fiber, and 24.6V/m for a 5 □m diameter fiber, assuming a pulse width that is within thecontemplated range of the present invention (1 ms). It is understoodthat these thresholds may differ slightly from those produced by thewaveform of the present invention as illustrated by REILLY's figures,for example, because the present invention prefers to use sinusoidalrather than square pulses. Thresholds for B and C fibers arerespectively 2 to 3 and 10 to100 times greater than those for A fibers[Mark A. CASTORO, Paul B. Yoo, Juan G. Hincapie, Jason J. Hamann,Stephen B. Ruble, Patrick D. Wolf, Warren M. Grill. Excitationproperties of the right cervical vagus nerve in adult dogs. ExperimentalNeurology 227 (2011): 62-68]. If we assume an average A fiber thresholdof 15 V/m, then B fibers would have thresholds of 30 to 45 V/m and Cfibers would have thresholds of 150 to 1500 V/m. The present inventionproduces electric fields at the vagus nerve in the range of about 6 to100 V/m, which is therefore generally sufficient to excite allmyelinated A and B fibers, but not the unmyelinated C fibers. Incontrast, invasive vagus nerve stimulators that have been used for thetreatment of epilepsy have been reported to excite C fibers in somepatients [EVANS M S, Verma-Ahuja S, Naritoku D K, Espinosa J A.Intraoperative human vagus nerve compound action potentials. Acta NeurolScand 110(2004): 232-238].

It is understood that although devices of the present invention maystimulate A and B nerve fibers, in practice they may also be used so asnot to stimulate the largest A fibers (A-delta) and B fibers. Inparticular, if the stimulator amplitude has been increased to the pointat which unwanted side effects begin to occur, the operator of thedevice may simply reduce the amplitude to avoid those effects. Forexample, vagal efferent fibers responsible for bronchoconstriction havebeen observed to have conduction velocities in the range of those of Bfibers. In those experiments, bronchoconstriction was only produced whenB fibers were activated, and became maximal before C fibers had beenrecruited [R. M. McALLEN and K. M. Spyer. Two types of vagalpreganglionic motoneurones projecting to the heart and lungs. J.Physiol. 282(1978): 353-364]. Because proper stimulation with thedisclosed devices does not result in the side-effect ofbronchoconstriction, evidently the bronchoconstrictive B-fibers arepossibly not being activated when the amplitude is properly set. Also,the absence of bradycardia or prolongation of PR interval suggests thatcardiac efferent B-fibers are not stimulated. Similarly, A-deltaafferents may behave physiologically like C fibers. Because stimulationwith the disclosed devices does not produce nociceptive effects thatwould be produced by jugular A-delta fibers or C fibers, evidently theA-delta fibers may not be stimulated when the amplitude is properly set.

To summarize the foregoing discussion, the delivery, in a patientsuffering from autism spectrum disorders, of an impulse of energysufficient to stimulate and/or modulate transmission of signals of vagusnerve fibers will result in improved excitation-inhibition balance andmore normal activity within higher centers of the brain (e.g.,interoception), many of which are components of resting state networks.The most likely mechanisms do not involve the stimulation of C fibers;and the stimulation of afferent nerve fibers activates neural pathwayscauses the release of norepinephrine, and/or serotonin and/or GABA.

The use of feedback to generate the modulation signal 400 may result ina signal that is not periodic, particularly if the feedback is producedfrom sensors that measure naturally occurring, time-varying aperiodicphysiological signals from the patient (see FIG. 8 ). In fact, theabsence of significant fluctuation in naturally occurring physiologicalsignals from a patient is ordinarily considered to be an indication thatthe patient is in ill health. This is because a pathological controlsystem that regulates the patient's physiological variables may havebecome trapped around only one of two or more possible steady states andis therefore unable to respond normally to external and internalstresses. Accordingly, even if feedback is not used to generate themodulation signal 400, it may be useful to artificially modulate thesignal in an aperiodic fashion, in such a way as to simulatefluctuations that would occur naturally in a healthy individual. Thus,the noisy modulation of the stimulation signal may cause a pathologicalphysiological control system to be reset or undergo a non-linear phasetransition, through a mechanism known as stochastic resonance [B. SUKI,A. Alencar, M. K. Sujeer, K. R. Lutchen, J. J. Collins, J. S. Andrade,E. P. Ingenito, S. Zapperi, H. E. Stanley, Life-support system benefitsfrom noise, Nature 393 (1998) 127-128; W Alan C MUTCH, M Ruth Graham,Linda G Girling and John F Brewster. Fractal ventilation enhancesrespiratory sinus arrhythmia. Respiratory Research 2005, 6:41, pp. 1-9].

So, in one embodiment of the present invention, the modulation signal400, with or without feedback, will stimulate the selected nerve fibersin such a way that one or more of the stimulation parameters (power,frequency, and others mentioned herein) are varied by sampling astatistical distribution having a mean corresponding to a selected, orto a most recent running-averaged value of the parameter, and thensetting the value of the parameter to the randomly sampled value. Thesampled statistical distributions will comprise Gaussian and 1/f,obtained from recorded naturally occurring random time series or bycalculated formula. Parameter values will be so changed periodically, orat time intervals that are themselves selected randomly by samplinganother statistical distribution, having a selected mean and coefficientof variation, where the sampled distributions comprise Gaussian andexponential, obtained from recorded naturally occurring random timeseries or by calculated formula.

In another embodiment, devices in accordance with the present inventionare provided in a “pacemaker” type form, in which electrical impulses410 are generated to a selected region of the nerve by a stimulatordevice on an intermittent basis, to create in the patient a lowerreactivity of the nerve.

Preferred Embodiments of the Magnetic Stimulator

A preferred embodiment of magnetic stimulator coil 341 comprises atoroidal winding around a core consisting of high-permeability material(e.g., Supermendur), embedded in an electrically conducting medium.Toroidal coils with high permeability cores have been theoreticallyshown to greatly reduce the currents required for transcranial (TMS) andother forms of magnetic stimulation, but only if the toroids areembedded in a conducting medium and placed against tissue with no airinterface [Rafael CARBUNARU and Dominique M. Durand. Toroidal coilmodels for transcutaneous magnetic stimulation of nerves. IEEETransactions on Biomedical Engineering 48 (4, 2001): 434-441; RafaelCarbunaru FAIERSTEIN, Coil Designs for Localized and Efficient MagneticStimulation of the Nervous System. Ph.D. Dissertation, Department ofBiomedical Engineering, Case Western Reserve, May, 1999, (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor Mich.)].

Although Carbunaru and Durand demonstrated that it is possible toelectrically stimulate a patient transcutaneously with such a device,they made no attempt to develop the device in such a way as to generallyshape the electric field that is to stimulate the nerve. In particular,the electric fields that may be produced by their device are limited tothose that are radially symmetric at any given depth of stimulation intothe patient (i.e, z and □□ are used to specify location of the field,not x, y, and z). This is a significant limitation, and it results in adeficiency that was noted in FIG. 6 of their publication: “at largedepths of stimulation, the threshold current [in the device's coil] forlong axons is larger than the saturation current of the coil.Stimulation of those axons is only possible at low threshold points suchas bending sites or tissue conductivity inhomogeneities”. Thus, fortheir device, varying the parameters that they considered, in order toincrease the electric field or its gradient in the vicinity of a nerve,may come at the expense of limiting the field's physiologicaleffectiveness, such that the spatial extent of the field of stimulationmay be insufficient to modulate the target nerve's function. Yet, suchlong axons are precisely what we may wish to stimulate in therapeuticinterventions, such as the ones disclosed herein.

Accordingly, it is an objective of the present invention to shape anelongated electric field of effect that can be oriented parallel to sucha long nerve. The term “shape an electric field” as used herein means tocreate an electric field or its gradient that is generally not radiallysymmetric at a given depth of stimulation in the patient, especially afield that is characterized as being elongated or finger-like, andespecially also a field in which the magnitude of the field in somedirection may exhibit more than one spatial maximum (i.e. may be bimodalor multimodal) such that the tissue between the maxima may contain anarea across which induced current flow is restricted. Shaping of theelectric field refers both to the circumscribing of regions within whichthere is a significant electric field and to configuring the directionsof the electric field within those regions. The shaping of the electricfield is described in terms of the corresponding field equations incommonly assigned application US20110125203 (application Ser. No.12/964,050), entitled Magnetic stimulation devices and methods oftherapy, to SIMON et al., which is hereby incorporated by reference.

Thus, the present invention differs from the device disclosed byCARBUNARU and Durand by deliberately shaping an electric field that isused to transcutaneously stimulate the patient. Whereas the toroid inthe CARBUNARU and Durand publication was immersed in a homogeneousconducting half-space, this is not necessarily the case for ourinvention. Although our invention will generally have some continuouslyconducting path between the device's coil and the patient's skin, theconducting medium need not totally immerse the coil, and there may beinsulating voids within the conducting medium. For example, if thedevice contains two toroids, conducting material may connect each of thetoroids individually to the patient's skin, but there may be aninsulating gap (from air or some other insulator) between the surfacesat which conducting material connected to the individual toroids contactthe patient. Furthermore, the area of the conducting material thatcontacts the skin may be made variable, by using an aperture adjustingmechanism such as an iris diaphragm. As another example, if the coil iswound around core material that is laminated, with the core in contactwith the device's electrically conducting material, then the laminationmay be extended into the conducting material in such a way as to directthe induced electrical current between the laminations and towards thesurface of the patient's skin. As another example, the conductingmaterial may pass through apertures in an insulated mesh beforecontacting the patient's skin, creating thereby an array of electricfield maxima.

In the dissertation cited above, Carbunaru-FAIERSTEIN made no attempt touse conducting material other than agar in a KCl solution, and he madeno attempt to devise a device that could be conveniently and safelyapplied to a patient's skin, at an arbitrary angle without theconducting material spilling out of its container. It is therefore anobjective of the present invention to disclose conducting material thatcan be used not only to adapt the conductivity of the conductingmaterial and select boundary conditions, thereby shaping the electricfields and currents as described above, but also to create devices thatcan be applied practically to any surface of the body. The volume of thecontainer containing electrically conducting medium is labeled in FIG.2A as 351. Use of the container of conducting medium 351 allows one togenerate (induce) electric fields in tissue (and electric fieldgradients and electric currents) that are equivalent to those generatedusing current magnetic stimulation devices, but with about 0.001 to 0.1of the current conventionally applied to a magnetic stimulation coil.This allows for minimal heating of the coil(s) and deeper tissuestimulation. However, application of the conducting medium to thesurface of the patient is difficult to perform in practice because thetissue contours (head, arms, legs, neck, etc.) are not planar. To solvethis problem, in the preferred embodiment of the present invention, thetoroidal coil is embedded in a structure which is filled with aconducting medium having approximately the same conductivity as muscletissue, as now described.

In one embodiment of the invention, the container contains holes so thatthe conducting material (e.g., a conducting gel) can make physicalcontact with the patient's skin through the holes. For example, theconducting medium 351 may comprise a chamber surrounding the coil,filled with a conductive gel that has the approximate viscosity andmechanical consistency of gel deodorant (e.g., Right Guard Clear Gelfrom Dial Corporation, 15501 N. Dial Boulevard, Scottsdale Ariz. 85260,one composition of which comprises aluminum chlorohydrate, sorbitol,propylene glycol, polydimethylsiloxanes Silicon oil, cyclomethicone,ethanol/SD Alcohol 40, dimethicone copolyol, aluminum zirconiumtetrachlorohydrex gly, and water). The gel, which is less viscous thanconventional electrode gel, is maintained in the chamber with a mesh ofopenings at the end where the device is to contact the patient's skin.The gel does not leak out, and it can be dispensed with a simple screwdriven piston.

In another embodiment, the container itself is made of a conductingelastomer (e.g., dry carbon-filled silicone elastomer), and electricalcontact with the patient is through the elastomer itself, possiblythrough an additional outside coating of conducting material. In someembodiments of the invention, the conducting medium may be a balloonfilled with a conducting gel or conducting powders, or the balloon maybe constructed extensively from deformable conducting elastomers. Theballoon conforms to the skin surface, removing any air, thus allowingfor high impedance matching and conduction of large electric fields into the tissue. A device such as that disclosed in U.S. Pat. No.7,591,776, entitled Magnetic stimulators and stimulating coils, toPHILLIPS et al. may conform the coil itself to the contours of the body,but in the preferred embodiment, such a curved coil is also enclosed bya container that is filled with a conducting medium that deforms to becontiguous with the skin.

Agar can also be used as part of the conducting medium, but it is notpreferred, because agar degrades in time, is not ideal to use againstskin, and presents difficulties with cleaning the patient and stimulatorcoil. Use of agar in a 4M KCl solution as a conducting medium wasmentioned in the above-cited dissertation: Rafael Carbunaru FAIERSTEIN,Coil Designs for Localized and Efficient Magnetic Stimulation of theNervous System. Ph.D. Dissertation, Department of BiomedicalEngineering, Case Western Reserve, May, 1999, page 117 (UMI MicroformNumber: 9940153, UMI Company, Ann Arbor Mich.). However, thatpublication makes no mention or suggestion of placing the agar in aconducting elastomeric balloon, or other deformable container so as toallow the conducting medium to conform to the generally non-planarcontours of a patient's skin having an arbitrary orientation. In fact,that publication describes the coil as being submerged in a containerfilled with an electrically conducting solution. If the coil andcontainer were placed on a body surface that was oriented in thevertical direction, then the conducting solution would spill out, makingit impossible to stimulate the body surface in that orientation. Incontrast, the present invention is able to stimulate body surfaceshaving arbitrary orientation.

That dissertation also makes no mention of a dispensing method wherebythe agar would be made contiguous with the patient's skin. A layer ofelectrolytic gel is said to have been applied between the skin and coil,but the configuration was not described clearly in the publication. Inparticular, no mention is made of the electrolytic gel being in contactwith the agar.

Rather than using agar as the conducting medium, the coil can instead beembedded in a conducting solution such as 1-10% NaCl, contacting anelectrically conducting interface to the human tissue. Such an interfaceis used as it allows current to flow from the coil into the tissue andsupports the medium-surrounded toroid so that it can be completelysealed. Thus, the interface is material, interposed between theconducting medium and patient's skin, that allows the conducting medium(e.g., saline solution) to slowly leak through it, allowing current toflow to the skin. Several interfaces are disclosed as follows.

One interface comprises conducting material that is hydrophilic, such asTecophlic from The Lubrizol Corporation, 29400 Lakeland Boulevard,Wickliffe, Ohio 44092. It absorbs from 10-100% of its weight in water,making it highly electrically conductive, while allowing only minimalbulk fluid flow.

Another material that may be used as an interface is a hydrogel, such asthat used on standard EEG, EKG and TENS electrodes [Rylie A GREEN,Sungchul Baek, Laura A Poole-Warren and Penny J Martens. Conductingpolymer-hydrogels for medical electrode applications. Sci. Technol. Adv.Mater. 11 (2010) 014107 (13pp)]. For example it may be the followinghypoallergenic, bacteriostatic electrode gel: SIGNAGEL Electrode Gelfrom Parker Laboratories, Inc., 286 Eldridge Rd., Fairfield N.J. 07004.

A third type of interface may be made from a very thin material with ahigh dielectric constant, such as those used to make capacitors. Forexample, Mylar can be made in submicron thicknesses and has a dielectricconstant of about 3. Thus, at stimulation frequencies of severalkilohertz or greater, the Mylar will capacitively couple the signalthrough it because it will have an impedance comparable to that of theskin itself. Thus, it will isolate the toroid and the solution it isembedded in from the tissue, yet allow current to pass.

The preferred embodiment of the magnetic stimulator coil 341 in FIG. 2Areduces the volume of conducting material that must surround a toroidalcoil, by using two toroids, side-by-side, and passing electrical currentthrough the two toroidal coils in opposite directions. In thisconfiguration, the induced current will flow from the lumen of onetoroid, through the tissue and back through the lumen of the other,completing the circuit within the toroids' conducting medium. Thus,minimal space for the conducting medium is required around the outsideof the toroids at positions near from the gap between the pair of coils.An additional advantage of using two toroids in this configuration isthat this design will greatly increase the magnitude of the electricfield gradient between them, which is crucial for exciting long,straight axons such as the vagus nerve and certain other peripheralnerves.

This preferred embodiment of the magnetic stimulation device is shown inFIG. 3 . FIGS. 3A and 3B respectively provide top and bottom views ofthe outer surface of the toroidal magnetic stimulator 30. FIGS. 3C and3D respectively provide top and bottom views of the toroidal magneticstimulator 30, after sectioning along its long axis to reveal the insideof the stimulator.

FIGS. 3A-3D all show a mesh 31 with openings that permit a conductinggel to pass from the inside of the stimulator to the surface of thepatient's skin at the location of nerve or tissue stimulation. Thus, themesh with openings 31 is the part of the stimulator that is applied tothe skin of the patient.

FIGS. 3B-3D show openings at the opposite end of the stimulator 30. Oneof the openings is an electronics port 32 through which wires pass fromthe stimulator coil(s) to the impulse generator (310 in FIG. 2A). Thesecond opening is a conducting gel port 33 through which conducting gelmay be introduced into the stimulator 30 and through which ascrew-driven piston arm may be introduced to dispense conducting gelthrough the mesh 31. The gel itself will be contained withincylindrical-shaped but interconnected conducting medium chambers 34 thatare shown in FIGS. 3C and 3D. The depth of the conducting mediumchambers 34, which is approximately the height of the long axis of thestimulator, affects the magnitude of the electric fields and currentsthat are induced by the device [Rafael CARBUNARU and Dominique M.Durand. Toroidal coil models for transcutaneous magnetic stimulation ofnerves. IEEE Transactions on Biomedical Engineering. 48 (4, 2001):434-441].

FIGS. 3C and 3D also show the coils of wire 35 that are wound aroundtoroidal cores 36, consisting of high-permeability material (e.g.,Supermendur). Lead wires (not shown) for the coils 35 pass from thestimulator coil(s) to the impulse generator (310 in FIG. 1 ) via theelectronics port 32. Different circuit configurations are contemplated.If separate lead wires for each of the coils 35 connect to the impulsegenerator (i.e., parallel connection), and if the pair of coils arewound with the same handedness around the cores, then the design is forcurrent to pass in opposite directions through the two coils. On theother hand, if the coils are wound with opposite handedness around thecores, then the lead wires for the coils may be connected in series tothe impulse generator, or if they are connected to the impulse generatorin parallel, then the design is for current to pass in the samedirection through both coils.

As seen in FIGS. 3C and 3D, the coils 35 and cores 36 around which theyare wound are mounted as close as practical to the corresponding mesh 31with openings through which conducting gel passes to the surface of thepatient's skin. As seen in FIG. 3D, each coil and the core around whichit is wound is mounted in its own housing 37, the function of which isto provide mechanical support to the coil and core, as well as toelectrically insulate a coil from its neighboring coil. With thisdesign, induced current will flow from the lumen of one toroid, throughthe tissue and back through the lumen of the other, completing thecircuit within the toroids' conducting medium.

Different diameter toroidal coils and windings may be preferred fordifferent applications. For a generic application, the outer diameter ofthe core may be typically 1 to 5 cm, with an inner diameter typically0.5 to 0.75 of the outer diameter. The coil's winding around the coremay be typically 3 to 250 in number, depending on the core diameter anddepending on the desired coil inductance.

Signal generators for magnetic stimulators have been described forcommercial systems [Chris HOVEY and Reza Jalinous, THE GUIDE TO MAGNETICSTIMULATION, The Magstim Company Ltd, Spring Gardens, Whitland,Carmarthenshire, SA34 OHR, United Kingdom, 2006], as well as for customdesigns for a control unit 330, impulse generator 310 and power source320 [Eric BASHAM, Zhi Yang, Natalia Tchemodanov, and Wentai Liu.Magnetic Stimulation of Neural Tissue: Techniques and System Design. pp293-352, In: Implantable Neural Prostheses 1, Devices and Applications,D. Zhou and E. Greenbaum, eds., New York: Springer (2009); U.S. Pat. No.7,744,523, entitled Drive circuit for magnetic stimulation, to CharlesM. Epstein; U.S. Pat. No. 5,718,662, entitled Apparatus for the magneticstimulation of cells or tissue, to Reza Jalinous; U.S. Pat. No.5,766,124, entitled Magnetic stimulator for neuro-muscular tissue, toPoison]. Conventional magnetic nerve stimulators use a high currentimpulse generator that may produce discharge currents of 5,000 amps ormore, which is passed through the stimulator coil, and which therebyproduces a magnetic pulse. Typically, a transformer charges a capacitorin the impulse generator 310, which also contains circuit elements thatlimit the effect of undesirable electrical transients. Charging of thecapacitor is under the control of a control unit 330, which acceptsinformation such as the capacitor voltage, power and other parametersset by the user, as well as from various safety interlocks within theequipment that ensure proper operation, and the capacitor is thendischarged through the coil via an electronic switch (e.g., a controlledrectifier) when the user wishes to apply the stimulus.

Greater flexibility is obtained by adding to the impulse generator abank of capacitors that can be discharged at different times. Thus,higher impulse rates may be achieved by discharging capacitors in thebank sequentially, such that recharging of capacitors is performed whileother capacitors in the bank are being discharged. Furthermore, bydischarging some capacitors while the discharge of other capacitors isin progress, by discharging the capacitors through resistors havingvariable resistance, and by controlling the polarity of the discharge,the control unit may synthesize pulse shapes that approximate anarbitrary function.

The design and methods of use of impulse generators, control units, andstimulator coils for magnetic stimulators are informed by the designsand methods of use of impulse generators, control units, and electrodes(with leads) for comparable completely electrical nerve stimulators, butdesign and methods of use of the magnetic stimulators must take intoaccount many special considerations, making it generally notstraightforward to transfer knowledge of completely electricalstimulation methods to magnetic stimulation methods. Such considerationsinclude determining the anatomical location of the stimulation anddetermining the appropriate pulse configuration [OLNEY RK, So Y T,Goodin D S, Aminoff M J. A comparison of magnetic and electricstimulation of peripheral nerves. Muscle Nerve 1990:13:957-963; J.NILSSON, M. Panizza, B. J. Roth et al. Determining the site ofstimulation during magnetic stimulation of the peripheral nerve,Electroencephalographs and clinical neurophysiology 85(1992): 253-264;Nafia A L-MUTAWALY, Hubert de Bruin, and Gary Hasey. The effects ofpulse configuration on magnetic stimulation. Journal of ClinicalNeurophysiology 20(5):361-370, 2003].

Furthermore, a potential practical disadvantage of using magneticstimulator coils is that they may overheat when used over an extendedperiod of time. Use of the above-mentioned toroidal coil and containerof electrically conducting medium addresses this potential disadvantage.However, because of the poor coupling between the stimulating coils andthe nerve tissue, large currents are nevertheless required to reachthreshold electric fields. At high repetition rates, these currents canheat the coils to unacceptable levels in seconds to minutes depending onthe power levels and pulse durations and rates. Two approaches toovercome heating are to cool the coils with flowing water or air or toincrease the magnetic fields using ferrite cores (thus allowing smallercurrents). For some applications where relatively long treatment timesat high stimulation frequencies may be required, neither of these twoapproaches are adequate. Water-cooled coils overheat in a few minutes.Ferrite core coils heat more slowly due to the lower currents and heatcapacity of the ferrite core, but also cool off more slowly and do notallow for water-cooling since the ferrite core takes up the volume wherethe cooling water would flow.

A solution to this problem is to use a fluid which containsferromagnetic particles in suspension like a ferrofluid, ormagnetorheological fluid as the cooling material. Ferrofluids arecolloidal mixtures composed of nanoscale ferromagnetic, orferrimagnetic, particles suspended in a carrier fluid, usually anorganic solvent or water. The ferromagnetic nanoparticles are coatedwith a surfactant to prevent their agglomeration (due to van der Waalsforces and magnetic forces). Ferrofluids have a higher heat capacitythan water and will thus act as better coolants. In addition, the fluidwill act as a ferrite core to increase the magnetic field strength.Also, since ferrofluids are paramagnetic, they obey Curie's law, andthus become less magnetic at higher temperatures. The strong magneticfield created by the magnetic stimulator coil will attract coldferrofluid more than hot ferrofluid thus forcing the heated ferrofluidaway from the coil. Thus, cooling may not require pumping of theferrofluid through the coil, but only a simple convective system forcooling. This is an efficient cooling method which may require noadditional energy input [U.S. Pat. No. 7,396,326 and publishedapplications US2008/0114199, US2008/0177128, and US2008/0224808, allentitled Ferrofluid cooling and acoustical noise reduction in magneticstimulators, respectively to Ghiron et al., Riehl et al., Riehl et al.and Ghiron et al.].

Magnetorheological fluids are similar to ferrofluids but contain largermagnetic particles which have multiple magnetic domains rather than thesingle domains of ferrofluids. [U.S. Pat. No. 6,743,371, Magnetosensitive fluid composition and a process for preparation thereof, toJohn et al.]. They can have a significantly higher magnetic permeabilitythan ferrofluids and a higher volume fraction of iron to carrier.Combinations of magnetorheological and ferrofluids may also be used [M TLOPEZ-LOPEZ, P Kuzhir, S Lacis, G Bossis, F Gonzalez-Caballero and J D GDuran. Magnetorheology for suspensions of solid particles dispersed inferrofluids. J. Phys.: Condens. Matter 18 (2006) S2803-S2813; LadislauVEKAS. Ferrofluids and Magnetorheological Fluids. Advances in Scienceand Technology Vol. 54 (2008) pp 127-136.].

Commercially available magnetic stimulators include circular, parabolic,figure-of-eight (butterfly), and custom designs that are availablecommercially [Chris HOVEY and Reza Jalinous, THE GUIDE TO MAGNETICSTIMULATION, The Magstim Company Ltd, Spring Gardens, Whitland,Carmarthenshire, SA34 0HR, United Kingdom, 2006]. Additional embodimentsof the magnetic stimulator coil 341 have been described [U.S. Pat. No.6,179,770, entitled Coil assemblies for magnetic stimulators, to StephenMould; Kent DAVEY. Magnetic Stimulation Coil and Circuit Design. IEEETransactions on Biomedical Engineering, Vol. 47 (No. 11, November 2000):1493-1499]. Many of the problems that are associated with suchconventional magnetic stimulators, e.g., the complexity of theimpulse-generator circuitry and the problem with overheating, arelargely avoided by the toroidal design shown in FIG. 3 .

Thus, use of the container of conducting medium 351 allows one togenerate (induce) electric fields in tissue (and electric fieldgradients and electric currents) that are equivalent to those generatedusing current magnetic stimulation devices, but with about 0.001 to 0.1of the current conventionally applied to a magnetic stimulation coil.Therefore, with the present invention, it is possible to generatewaveforms shown in FIG. 2 with relatively simple, low-power circuitsthat are powered by batteries. The circuits may be enclosed within a box38 as shown in FIG. 3E, or the circuits may be attached to thestimulator itself (FIG. 3A-3D) to be used as a hand-held device. Ineither case, control over the unit may be made using only an on/offswitch and power knob. The only other component that may be needed mightbe a cover 39 to keep the conducting fluid from leaking or drying outbetween uses. The currents passing through the coils of the magneticstimulator will saturate its core (e.g., 0.1 to 2 Tesla magnetic fieldstrength for Supermendur core material). This will require approximately0.5 to 20 amperes of current being passed through each coil, typically 2amperes, with voltages across each coil of 10 to100 volts. The currentis passed through the coils in bursts of pulses, as described inconnection with FIGS. 2D and 2E, shaping an elongated electrical fieldof effect.

Preferred Embodiments of the Electrode-Based Stimulator

In another embodiment of the invention, electrodes applied to thesurface of the neck, or to some other surface of the body, are used tonon-invasively deliver electrical energy to a nerve, instead ofdelivering the energy to the nerve via a magnetic coil. The vagus nervehas been stimulated previously non-invasively using electrodes appliedvia leads to the surface of the skin. It has also been stimulatednon-electrically through the use of mechanical vibration [HUSTON J M,Gallowitsch-Puerta M, Ochani M, Ochani K, Yuan R, Rosas-Ballina M et al(2007). Transcutaneous vagus nerve stimulation reduces serum highmobility group box 1 levels and improves survival in murine sepsis. CritCare Med35: 2762-2768; GEORGE M S, Aston-Jones G. Noninvasive techniquesfor probing neurocircuitry and treating illness: vagus nerve stimulation(VNS), transcranial magnetic stimulation (TMS) and transcranial directcurrent stimulation (tDCS). Neuropsychopharmacology 35(1,2010):301-316]. However, no such reported uses of noninvasive vagusnerve stimulation were directed to the treatment of autisticindividuals. U.S. Pat. No. 7,340,299, entitled Methods of indirectlystimulating the vagus nerve to achieve controlled asystole, to John D.PUSKAS, discloses the stimulation of the vagus nerve using electrodesplaced on the neck of the patient, but that patent is unrelated to thetreatment of autism spectrum disorders. Non-invasive electricalstimulation of the vagus nerve has also been described in Japanesepatent application JP2009233024A with a filing date of Mar. 26, 2008,entitled Vagus Nerve Stimulation System, to Fukui YOSHIHOTO, in which abody surface electrode is applied to the neck to stimulate the vagusnerve electrically. However, that application pertains to the control ofheart rate and is unrelated to the treatment of autism spectrumdisorders. In patent publication US20080208266, entitled System andmethod for treating nausea and vomiting by vagus nerve stimulation, toLESSER et al., electrodes are used to stimulate the vagus nerve in theneck to reduce nausea and vomiting, but this too is unrelated to thetreatment of autism.

Patent application US2010/0057154, entitled Device and method for thetransdermal stimulation of a nerve of the human body, to DIETRICH etal., discloses a non-invasive transcutaneous/transdermal method forstimulating the vagus nerve, at an anatomical location where the vagusnerve has paths in the skin of the external auditory canal. Theirnon-invasive method involves performing electrical stimulation at thatlocation, using surface stimulators that are similar to those used forperipheral nerve and muscle stimulation for treatment of pain(transdermal electrical nerve stimulation), muscle training (electricalmuscle stimulation) and electroacupuncture of defined meridian points.The method used in that application is similar to the ones used in U.S.Pat. No. 4,319,584, entitled Electrical pulse acupressure system, toMcCALL, for electroacupuncture; U.S. Pat. No. 5,514,175 entitledAuricular electrical stimulator, to KIM et al., for the treatment ofpain; and U.S. Pat. No. 4,966,164, entitled Combined sound generatingdevice and electrical acupuncture device and method for using the same,to COLSEN et al., for combined sound/electroacupuncture. A relatedapplication is US2006/0122675, entitled Stimulator for auricular branchof vagus nerve, to LIBBUS et al. Similarly, U.S. Pat. No. 7,386,347,entitled Electric stimilator for alpha-wave derivation, to CHUNG et al.,described electrical stimulation of the vagus nerve at the ear. Patentapplication US2008/0288016, entitled Systems and Methods for StimulatingNeural Targets, to AMURTHUR et al., also discloses electricalstimulation of the vagus nerve at the ear. U.S. Pat. No. 4,865,048,entitled Method and apparatus for drug free neurostimulation, toECKERSON, teaches electrical stimulation of a branch of the vagus nervebehind the ear on the mastoid processes, in order to treat symptoms ofdrug withdrawal. KRAUS et al described similar methods of stimulation atthe ear [KRAUS T, Hosl K, Kiess O, Schanze A, Kornhuber J, Forster C(2007). BOLD fMRI deactivation of limbic and temporal brain structuresand mood enhancing effect by transcutaneous vagus nerve stimulation. JNeural Transm 114: 1485-1493]. However, none of the disclosures in thesepatents or patent applications for electrical stimulation of the vagusnerve at the ear are used to treat autism spectrum disorders.

Embodiments of the present invention may differ with regard to thenumber of electrodes that are used, the distance between electrodes, andwhether disk or ring electrodes are used. In preferred embodiments ofthe method, one selects the electrode configuration for individualpatients, in such a way as to optimally focus electric fields andcurrents onto the selected nerve, without generating excessive currentson the surface of the skin. This tradeoff between focality and surfacecurrents is described by DATTA et al. [Abhishek DATTA, Maged Elwassif,Fortunato Battaglia and Marom Bikson. Transcranial current stimulationfocality using disc and ring electrode configurations: FEM analysis. J.Neural Eng. 5 (2008): 163-174]. Although DATTA et al. are addressing theselection of electrode configuration specifically for transcranialcurrent stimulation, the principles that they describe are applicable toperipheral nerves as well [RATTAY F. Analysis of models forextracellular fiber stimulation. IEEE Trans. Biomed. Eng. 36 (1989):676-682].

Considering that the nerve stimulating device 301 in FIG. 2A and thenerve stimulating device 302 in FIG. 2B both control the shape ofelectrical impulses, their functions are analogous, except that onestimulates nerves via a pulse of a magnetic field, and the otherstimulates nerves via an electrical pulse applied through surfaceelectrodes. Accordingly, general features recited for the nervestimulating device 301 apply as well to the latter stimulating device302 and will not be repeated here. The preferred parameters for eachnerve stimulating device are those that produce the desired therapeuticeffects.

A preferred embodiment of an electrode-based stimulator is shown in FIG.4A. A cross-sectional view of the stimulator along its long axis isshown in FIG. 4B. As shown, the stimulator (730) comprises two heads(731) and a body (732) that joins them. Each head (731) contains astimulating electrode. The body of the stimulator (732) contains theelectronic components and battery (not shown) that are used to generatethe signals that drive the electrodes, which are located behind theinsulating board (733) that is shown in FIG. 4B. However, in otherembodiments of the invention, the electronic components that generatethe signals that are applied to the electrodes may be separate, butconnected to the electrode head (731) using wires. Furthermore, otherembodiments of the invention may contain a single such head or ore thantwo heads.

Heads of the stimulator (731) are applied to a surface of the patient'sbody, during which time the stimulator may be held in place by straps orframes or collars, or the stimulator may be held against the patient'sbody by hand. In either case, the level of stimulation power may beadjusted with a wheel (734) that also serves as an on/off switch. Alight (735) is illuminated when power is being supplied to thestimulator. An optional cap may be provided to cover each of thestimulator heads (731), to protect the device when not in use, to avoidaccidental stimulation, and to prevent material within the head fromleaking or drying. Thus, in this embodiment of the invention, mechanicaland electronic components of the stimulator (impulse generator, controlunit, and power source) are compact, portable, and simple to operate.Details of one embodiment of the stimulator head are shown in FIGS. 4Cand 4D. The electrode head may be assembled from a disc withoutfenestration (743), or alternatively from a snap-on cap that serves as atambour for a dielectric or conducting membrane, or alternatively thehead may have a solid fenestrated head-cup. The electrode may also be ascrew (745). The preferred embodiment of the disc (743) is a solid,ordinarily uniformly conducting disc (e.g., metal such as stainlesssteel), which is possibly flexible in some embodiments. An alternateembodiment of the disc is a non-conducting (e.g., plastic) aperturescreen that permits electrical current to pass through its apertures,e.g., through an array of apertures (fenestration). The electrode (745,also 340 in FIG. 2B) seen in each stimulator head may have the shape ofa screw that is flattened on its tip. Pointing of the tip would make theelectrode more of a point source, such that the equations for theelectrical potential may have a solution corresponding more closely to afar-field approximation. Rounding of the electrode surface or making thesurface with another shape will likewise affect the boundary conditionsthat determine the electric field. Completed assembly of the stimulatorhead is shown in FIG. 4D, which also shows how the head is attached tothe body of the stimulator (747).

If a membrane is used, it ordinarily serves as the interface shown as351 in FIG. 2B. For example, the membrane may be made of a dielectric(non-conducting) material, such as a thin sheet of Mylar(biaxially-oriented polyethylene terephthalate, also known as BoPET). Inother embodiments, it may be made of conducting material, such as asheet of Tecophlic material from Lubrizol Corporation, 29400 LakelandBoulevard, Wickliffe, Ohio 44092. In one embodiment, apertures of thedisc may be open, or they may be plugged with conducting material, forexample, KM10T hydrogel from Katecho Inc., 4020 Gannett Ave., Des MoinesIowa 50321. If the apertures are so-plugged, and the membrane is made ofconducting material, the membrane becomes optional, and the plug servesas the interface 351 shown in FIG. 2B. The head-cup (744) is filled withconducting material (350 in FIG. 2B), for example, SIGNAGEL ElectrodeGel from Parker Laboratories, Inc., 286 Eldridge Rd., Fairfield N.J.07004. The head-cup (744) and body of the stimulator are made of anon-conducting material, such as acrylonitrile butadiene styrene. Thedepth of the head-cup from its top surface to the electrode may bebetween one and six centimeters. The head-cup may have a differentcurvature than what is shown in FIG. 4 , or it may be tubular or conicalor have some other inner surface geomety that will affect the Neumannboundary conditions that determine the electric field strength.

If an outer membrane is used and is made of conducting materials, andthe disc (743) in FIG. 4C is made of solid conducting materials such asstainless steel, then the membrane becomes optional, in which case thedisc may serve as the interface 351 shown in FIG. 2B. Thus, anembodiment without the membrane is shown in FIGS. 4C and 4D. Thisversion of the device comprises a solid (but possibly flexible in someembodiments) conducting disc that cannot absorb fluid, thenon-conducting stimulator head (744) into or onto which the disc isplaced, and the electrode (745), which is also a screw. It is understoodthat the disc (743) may have an anisotropic material or electricalstructure, for example, wherein a disc of stainless steel has a grain,such that the grain of the disc should be rotated about its location onthe stimulator head, in order to achieve optimal electrical stimulationof the patient. As seen in FIG. 4D, these items are assembled to becomea sealed stimulator head that is attached to the body of the stimulator(747). The disc (743) may screw into the stimulator head (744), it maybe attached to the head with adhesive, or it may be attached by othermethods that are known in the art. The chamber of the stimulatorhead-cup is filled with a conducting gel, fluid, or paste, and becausethe disc (743) and electrode (745) are tightly sealed against thestimulator head-cup (744), the conducting material within the stimulatorhead cannot leak out. In addition, this feature allows the user toeasily clean the outer surface of the device (e.g., with isopropylalcohol or similar disinfectant), avoiding potential contaminationduring subsequent uses of the device. In some embodiments, the interfacecomprises a fluid permeable material that allows for passage of currentthrough the permeable portions of the material. In these embodiments, aconductive medium (such as a gel) is preferably situated between theelectrode(s) and the permeable interface. The conductive medium providesa conductive pathway for electrons to pass through the permeableinterface to the outer surface of the interface and to the patient'sskin.

In other embodiments of the present invention, the interface (351 inFIG. 2B) is made from a very thin material with a high dielectricconstant, such as material used to make capacitors. For example, it maybe Mylar having a submicron thickness (preferably in the range 0.5 to1.5 microns) having a dielectric constant of about 3. Because one sideof Mylar is slick, and the other side is microscopically rough, thepresent invention contemplates two different configurations: one inwhich the slick side is oriented towards the patient's skin, and theother in which the rough side is so-oriented. Thus, at stimulationFourier frequencies of several kilohertz or greater, the dielectricinterface will capacitively couple the signal through itself, because itwill have an impedance comparable to that of the skin. Thus, thedielectric interface will isolate the stimulator's electrode from thetissue, yet allow current to pass. In one embodiment of the presentinvention, non-invasive electrical stimulation of a nerve isaccomplished essentially substantially capacitively, which reduces theamount of ohmic stimulation, thereby reducing the sensation the patientfeels on the tissue surface. This would correspond to a situation, forexample, in which at least 30%, preferably at least 50%, of the energystimulating the nerve comes from capacitive coupling through thestimulator interface, rather than from ohmic coupling. In other words, asubstantial portion (e.g., 50%) of the voltage drop is across thedielectric interface, while the remaining portion is through the tissue.

In certain exemplary embodiments, the interface and/or its underlyingmechanical support comprise materials that will also provide asubstantial or complete seal of the interior of the device. Thisinhibits any leakage of conducting material, such as gel, from theinterior of the device and also inhibits any fluids from entering thedevice. In addition, this feature allows the user to easily clean thesurface of the dielectric material (e.g., with isopropyl alcohol orsimilar disinfectant), avoiding potential contamination duringsubsequent uses of the device. One such material is a thin sheet ofMylar, supported by a stainless steel disc, as described above.

The selection of the material for the dielectric constant involves atleast two important variables: (1) the thickness of the interface; and(2) the dielectric constant of the material. The thinner the interfaceand/or the higher the dielectric constant of the material, the lower thevoltage drop across the dielectric interface (and thus the lower thedriving voltage required). For example, with Mylar, the thickness couldbe about 0.5 to 5 microns (preferably about 1 micron) with a dielectricconstant of about 3. For a piezoelectric material like barium titanateor PZT (lead zirconate titanate), the thickness could be about 100-400microns (preferably about 200 microns or 0.2 mm) because the dielectricconstant is >1000.

One of the novelties of the embodiment that is a non-invasive capacitivestimulator (hereinafter referred to more generally as a capacitiveelectrode) arises in that it uses a low voltage (generally less than 100volt) power source, which is made possible by the use of a suitablestimulation waveform, such as the waveform that is disclosed herein(FIG. 2 ). In addition, the capacitive electrode allows for the use ofan interface that provides a more adequate seal of the interior of thedevice. The capacitive electrode may be used by applying a small amountof conductive material (e.g., conductive gel as described above) to itsouter surface. In some embodiments, it may also be used by contactingdry skin, thereby avoiding the inconvenience of applying an electrodegel, paste, or other electrolytic material to the patient's skin andavoiding the problems associated with the drying of electrode pastes andgels. Such a dry electrode would be particularly suitable for use with apatient who exhibits dermatitis after the electrode gel is placed incontact with the skin [Ralph J. COSKEY. Contact dermatitis caused by ECGelectrode jelly. Arch Dermatol 113(1977): 839-840]. The capacitiveelectrode may also be used to contact skin that has been wetted (e.g.,with tap water or a more conventional electrolyte material) to make theelectrode-skin contact (here the dielectric constant) more uniform [A LALEXELONESCU, G Barbero, F C M Freire, and R Merletti. Effect ofcomposition on the dielectric properties of hydrogels for biomedicalapplications. Physiol. Meas. 31 (2010) S169-S182].

As described below, capacitive biomedical electrodes are known in theart, but when used to stimulate a nerve noninvasively, a high voltagepower supply is currently used to perform the stimulation. Otherwise,prior use of capacitive biomedical electrodes has been limited toinvasive, implanted applications; to non-invasive applications thatinvolve monitoring or recording of a signal, but not stimulation oftissue; to non-invasive applications that involve the stimulation ofsomething other than a nerve (e.g., tumor); or as the dispersiveelectrode in electrosurgery.

Evidence of a long-felt but unsolved need, and evidence of failure ofothers to solve the problem that is solved by the this embodiment of thepresent invention (low-voltage, non-invasive capacitive stimulation of anerve), is provided by KELLER and Kuhn, who review the previoushigh-voltage capacitive stimulating electrode of GEDDES et al and writethat “Capacitive stimulation would be a preferred way of activatingmuscle nerves and fibers, when the inherent danger of high voltagebreakdowns of the dielectric material can be eliminated. Goal of futureresearch could be the development of improved and ultra-thin dielectricfoils, such that the high stimulation voltage can be lowered.” [L. A.GEDDES, M. Hinds, and K. S. Foster. Stimulation with capacitorelectrodes. Medical and Biological Engineering and Computing 25(1987):359-360; Thierry KELLER and Andreas Kuhn. Electrodes for transcutaneous(surface) electrical stimulation. Journal of Automatic Control,University of Belgrade 18(2, 2008):35-45, on page 39]. It is understoodthat in the United States, according to the 2005 National ElectricalCode, high voltage is any voltage over 600 volts. U.S. Pat. No.3,077,884, entitled Electro-physiotherapy apparatus, to BARTROW et al,U.S. Pat. No. 4,144,893, entitled Neuromuscular therapy device, toHICKEY and U.S. Pat. No. 7,933,648, entitled High voltage transcutaneouselectrical stimulation device and method, to TANRISEVER, also describehigh voltage capacitive stimulation electrodes. U.S. Pat. No. 7,904,180,entitled Capacitive medical electrode, to JUOLA et al, describes acapacitive electrode that includes transcutaneous nerve stimulation asone intended application, but that patent does not describe stimulationvoltages or stimulation waveforms and frequencies that are to be usedfor the transcutaneous stimulation. U.S. Pat. No. 7,715,921, entitledElectrodes for applying an electric field in-vivo over an extendedperiod of time, to PALTI, and U.S. Pat. No. 7,805,201, entitled Treatinga tumor or the like with an electric field, to PALTI, also describecapacitive stimulation electrodes, but they are intended for thetreatment of tumors, do not disclose uses involving nerves, and teachstimulation frequencies in the range of 50 kHz to about 500 kHz.

This embodiment of the present invention uses a different method tolower the high stimulation voltage than developing ultra-thin dielectricfoils, namely, to use a suitable stimulation waveform, such as thewaveform that is disclosed herein (FIG. 2 ). That waveform hassignificant Fourier components at higher frequencies than waveforms usedfor transcutaneous nerve stimulation as currently practiced. Thus, oneof ordinary skill in the art would not have combined the claimedelements, because transcutaneous nerve stimulation is performed withwaveforms having significant Fourier components only at lowerfrequencies, and noninvasive capacitive nerve stimulation is performedat higher voltages. In fact, the elements in combination do not merelyperform the function that each element performs separately. Thedielectric material alone may be placed in contact with the skin inorder to perform pasteless or dry stimulation, with a more uniformcurrent density than is associated with ohmic stimulation, albeit withhigh stimulation voltages [L. A. GEDDES, M. Hinds, and K. S. Foster.Stimulation with capacitor electrodes. Medical and BiologicalEngineering and Computing 25(1987): 359-360; Yongmin KIM, H. GunterZieber, and Frank A. Yang. Uniformity of current density understimulating electrodes. Critical Reviews in Biomedical Engineering17(1990,6): 585-619]. With regard to the waveform element, a waveformthat has significant Fourier components at higher frequencies thanwaveforms currently used for transcutaneous nerve stimulation may beused to selectively stimulate a deep nerve and avoid stimulating othernerves, as disclosed herein for both noncapacitive and capacitiveelectrodes. But it is the combination of the two elements (dielectricinterface and waveform) that makes it possible to stimulate a nervecapacitively without using the high stimulation voltage as is currentlypracticed.

Another embodiment of the electrode-based stimulator is shown in FIG. 5, showing a device in which electrically conducting material isdispensed from the device to the patient's skin. In this embodiment, theinterface (351 in FIG. 2B) is the conducting material itself. FIGS. 5Aand 5B respectively provide top and bottom views of the outer surface ofthe electrical stimulator 50. FIG. 5C provides a bottom view of thestimulator 50, after sectioning along its long axis to reveal the insideof the stimulator.

FIGS. 5A and 5C show a mesh 51 with openings that permit a conductinggel to pass from inside of the stimulator to the surface of thepatient's skin at the position of nerve or tissue stimulation. Thus, themesh with openings 51 is the part of the stimulator that is applied tothe skin of the patient, through which conducting material may bedispensed. In any given stimulator, the distance between the two meshopenings 51 in FIG. 5A is constant, but it is understood that differentstimulators may be built with different inter-mesh distances, in orderto accommodate the anatomy and physiology of individual patients.Alternatively, the inter-mesh distance may be made variable as in theeyepieces of a pair of binoculars. A covering cap (not shown) is alsoprovided to fit snugly over the top of the stimulator housing and themesh openings 51, in order to keep the housing's conducting medium fromleaking or drying when the device is not in use.

FIGS. 5B and 5C show the bottom of the self-contained stimulator 50. Anon/off switch 52 is attached through a port 54, and a power-levelcontroller 53 is attached through another port 54. The switch isconnected to a battery power source (320 in FIG. 2B), and thepower-level controller is attached to the control unit (330 in FIG. 2B)of the device. The power source battery and power-level controller, aswell as the impulse generator (310 in FIG. 2B) are located (but notshown) in the rear compartment 55 of the housing of the stimulator 50.

Individual wires (not shown) connect the impulse generator (310 in FIG.2B) to the stimulator's electrodes 56. The two electrodes 56 are shownhere to be elliptical metal discs situated between the head compartment57 and rear compartment 55 of the stimulator 50. A partition 58separates each of the two head compartments 57 from one another and fromthe single rear compartment 55. Each partition 58 also holds itscorresponding electrode in place. However, each electrode 56 may beremoved to add electrically conducting gel (350 in FIG. 2B) to each headcompartment 57. An optional non-conducting variable-aperture irisdiaphragm may be placed in front of each of the electrodes within thehead compartment 57, in order to vary the effective surface area of eachof the electrodes. Each partition 58 may also slide towards the head ofthe device in order to dispense conducting gel through the meshapertures 51. The position of each partition 58 therefore determines thedistance 59 between its electrode 56 and mesh openings 51, which isvariable in order to obtain the optimally uniform current densitythrough the mesh openings 51. The outside housing of the stimulator 50,as well as each head compartment 57 housing and its partition 58, aremade of electrically insulating material, such as acrylonitrilebutadiene styrene, so that the two head compartments are electricallyinsulated from one another. Although the embodiment in FIG. 5 is shownto be a non-capacitive stimulator, it is understood that it may beconverted into a capacitive stimulator by replacing the mesh openings 51with a dielectric material, such as a sheet of Mylar, or by covering themesh openings 51 with a sheet of such dielectric material.

In preferred embodiments of the electrode-based stimulator shown in FIG.2B, electrodes are made of a metal, such as stainless steel, platinum,or a platinum-iridium alloy. However, in other embodiments, theelectrodes may have many other sizes and shapes, and they may be made ofother materials [Thierry KELLER and Andreas Kuhn. Electrodes fortranscutaneous (surface) electrical stimulation. Journal of AutomaticControl, University of Belgrade, 18(2, 2008):35-45; G. M. LYONS, G. E.Leane, M. Clarke-Moloney, J. V. O'Brien, P. A. Grace. An investigationof the effect of electrode size and electrode location on comfort duringstimulation of the gastrocnemius muscle. Medical Engineering & Physics26 (2004) 873-878; Bonnie J. FORRESTER and Jerrold S. Petrofsky. Effectof Electrode Size, Shape, and Placement During Electrical Stimulation.The Journal of Applied Research 4, (2, 2004): 346-354; Gad ALON, GideonKantor and Henry S. Ho. Effects of Electrode Size on Basic ExcitatoryResponses and on Selected Stimulus Parameters. Journal of Orthopaedicand Sports Physical Therapy. 20(1, 1994):29-35].

For example, the stimulator's conducting materials may be nonmagnetic,and the stimulator may be connected to the impulse generator by longnonmagnetic wires (345 in FIG. 2B), so that the stimulator may be usedin the vicinity of a strong magnetic field, possibly with added magneticshielding. As another example, there may be more than two electrodes;the electrodes may comprise multiple concentric rings; and theelectrodes may be disc-shaped or have a non-planar geometry. They may bemade of other metals or resistive materials such as silicon-rubberimpregnated with carbon that have different conductive properties[Stuart F. COGAN. Neural Stimulation and Recording Electrodes. Annu.Rev. Biomed. Eng. 2008. 10:275-309; Michael F. NOLAN. Conductivedifferences in electrodes used with transcutaneous electrical nervestimulation devices. Physical Therapy 71(1991):746-751].

Although the electrode may consist of arrays of conducting material, theembodiments shown in FIGS. 4 and 5 avoid the complexity and expense ofarray or grid electrodes [Ana POPOVIC-BIJELIC, Goran Bijelic, NikolaJorgovanovic, Dubravka Bojanic, Mirjana B. Popovic, and Dejan B.Popovic. Multi-Field Surface Electrode for Selective ElectricalStimulation. Artificial Organs 29 (6, 2005):448-452; Dejan B. POPOVICand Mirjana B. Popovic. Automatic determination of the optimal shape ofa surface electrode: Selective stimulation. Journal of NeuroscienceMethods 178 (2009) 174-181; Thierry KELLER, Marc Lawrence, Andreas Kuhn,and Manfred Morari. New Multi-Channel Transcutaneous ElectricalStimulation Technology for Rehabilitation. Proceedings of the 28th IEEEEMBS Annual International Conference New York City, USA, Aug. 30-Sep. 3,2006 (WeC14.5): 194-197]. This is because the designs shown in FIGS. 4and 5 provide a uniform surface current density, which would otherwisebe a potential advantage of electrode arrays, and which is a trait thatis not shared by most electrode designs [Kenneth R. BRENNEN. TheCharacterization of Transcutaneous Stimulating Electrodes. IEEETransactions on Biomedical Engineering BME-23 (4, 1976): 337-340; AndreiPATRICIU, Ken Yoshida, Johannes J. Struijk, Tim P. DeMonte, Michael L.G. Joy, and Hans Stødkilde-Jorgensen. Current Density Imaging andElectrically Induced Skin Burns Under Surface Electrodes. IEEETransactions on Biomedical Engineering 52 (12, 2005): 2024-2031; R. H.GEUZE. Two methods for homogeneous field defibrillation and stimulation.Med. and Biol. Eng. and Comput. 21(1983), 518-520; J. PETROFSKY, E.Schwab, M. Cuneo, J. George, J. Kim, A. Almalty, D. Lawson, E. Johnsonand W. Remigo. Current distribution under electrodes in relation tostimulation current and skin blood flow: are modern electrodes reallyproviding the current distribution during stimulation we believe theyare? Journal of Medical Engineering and Technology 30 (6, 2006):368-381; Russell G. MAUS, Erin M. McDonald, and R. Mark Wghtman. Imagingof Nonuniform Current Density at Microelectrodes by ElectrogeneratedChemiluminescence. Anal. Chem. 71(1999): 4944-4950]. In fact, patientsfound the design shown in FIGS. 4 and 5 to be less painful in a directcomparison with a commercially available grid-pattern electrode[UltraStim grid-pattern electrode, Axelggard Manufacturing Company, 520Industrial Way, Fallbrook Calif., 2011]. The embodiment of the electrodethat uses capacitive coupling is particularly suited to the generationof uniform stimulation currents [Yongmin KIM, H. Gunter Zieber, andFrank A. Yang. Uniformity of current density under stimulatingelectrodes. Critical Reviews in Biomedical Engineering 17(1990,6):585-619].

The electrode-based stimulator designs shown in FIGS. 4 and 5 situatethe electrode remotely from the surface of the skin within a chamber,with conducting material placed in the chamber between the skin andelectrode. Such a chamber design had been used prior to the availabilityof flexible, flat, disposable electrodes [U.S. Pat. No. 3,659,614,entitled Adjustable headband carrying electrodes for electricallystimulating the facial and mandibular nerves, to Jankelson; U.S. Pat.No. 3,590,810, entitled Biomedical body electode, to Kopecky; U.S. Pat.No. 3,279,468, entitled Electrotherapeutic facial mask apparatus, to LeVine; U.S. Pat. No. 6,757,556, entitled Electrode sensor, to Gopinathanet al; U.S. Pat. No. 4,383,529, entitled Iontophoretic electrode device,method and gel insert, to Webster; U.S. Pat. No. 4,220,159, entitledElectrode, to Francis et al. U.S. Pat. Nos. 3,862,633, 4,182,346, and3,973,557, entitled Electrode, to Allison et al; U.S. Pat. No.4,215,696, entitled Biomedical electrode with pressurized skin contact,to Bremer et al; and U.S. Pat. No. 4,166,457, entitled Fluidself-sealing bioelectrode, to Jacobsen et al.] The stimulator designsshown in FIGS. 4 and 5 are also self-contained units, housing theelectrodes, signal electronics, and power supply. Portable stimulatorsare also known in the art, for example, U.S. Pat. No. 7,171,266,entitled Electro-acupuncture device with stimulation electrode assembly,to Gruzdowich. One of the novelties of the designs shown in FIGS. 4 and5 is that the stimulator, along with a correspondingly suitablestimulation waveform, shapes the electric field, producing a selectivephysiological response by stimulating that nerve, but avoidingsubstantial stimulation of nerves and tissue other than the targetnerve, particularly avoiding the stimulation of nerves that producepain. The shaping of the electric field is described in terms of thecorresponding field equations in commonly assigned applicationUS20110230938 (application Ser. No. 13/075,746) entitled Devices andmethods for non-invasive electrical stimulation and their use for vagalnerve stimulation on the neck of a patient, to SIMON et al., which ishereby incorporated by reference.

In one embodiment, the magnetic stimulator coil 341 in FIG. 2A has abody that is similar to the electrode-based stimulator shown in FIG. 5C.To compare the electrode-based stimulator with the magnetic stimulator,refer to FIG. 5D, which shows the magnetic stimulator 530 sectionedalong its long axis to reveal its inner structure. As described below,it reduces the volume of conducting material that must surround atoroidal coil, by using two toroids, side-by-side, and passingelectrical current through the two toroidal coils in oppositedirections. In this configuration, the induced electrical current willflow from the lumen of one toroid, through the tissue and back throughthe lumen of the other, completing the circuit within the toroids'conducting medium. Thus, minimal space for the conducting medium isrequired around the outside of the toroids at positions near from thegap between the pair of coils. An additional advantage of using twotoroids in this configuration is that this design will greatly increasethe magnitude of the electric field gradient between them, which iscrucial for exciting long, straight axons such as the vagus nerve andcertain peripheral nerves.

As seen in FIG. 5D, a mesh 531 has openings that permit a conducting gel(within 351 in FIG. 2A) to pass from the inside of the stimulator to thesurface of the patient's skin at the location of nerve or tissuestimulation. Thus, the mesh with openings 531 is the part of themagnetic stimulator that is applied to the skin of the patient.

FIG. 5D also shows openings at the opposite end of the magneticstimulator 530. One of the openings is an electronics port 532 throughwhich wires pass from the stimulator coil(s) to the impulse generator(310 in FIG. 2A). The second opening is a conducting gel port 533through which conducting gel (351 in FIG. 2A) may be introduced into themagnetic stimulator 530 and through which a screw-driven piston arm maybe introduced to dispense conducting gel through the mesh 531. The gelitself is contained within cylindrical-shaped but interconnectedconducting medium chambers 534 that are shown in FIG. 5D. The depth ofthe conducting medium chambers 534, which is approximately the height ofthe long axis of the stimulator, affects the magnitude of the electricfields and currents that are induced by the magnetic stimulator device[Rafael CARBUNARU and Dominique M. Durand. Toroidal coil models fortranscutaneous magnetic stimulation of nerves. IEEE Transactions onBiomedical Engineering. 48 (4, 2001): 434-441].

FIG. 5D also show the coils of wire 535 that are wound around toroidalcores 536, consisting of high-permeability material (e.g., Supermendur).Lead wires (not shown) for the coils 535 pass from the stimulatorcoil(s) to the impulse generator (310 in FIG. 2A) via the electronicsport 532. Different circuit configurations are contemplated. If separatelead wires for each of the coils 535 connect to the impulse generator(i.e., parallel connection), and if the pair of coils are wound with thesame handedness around the cores, then the design is for current to passin opposite directions through the two coils. On the other hand, if thecoils are wound with opposite handedness around the cores, then the leadwires for the coils may be connected in series to the impulse generator,or if they are connected to the impulse generator in parallel, then thedesign is for current to pass in the same direction through both coils.As also seen in FIG. 5D, the coils 535 and cores 536 around which theyare wound are mounted as close as practical to the corresponding mesh531 with openings through which conducting gel passes to the surface ofthe patient's skin. As shown, each coil and the core around which it iswound is mounted in its own housing 537, the function of which is toprovide mechanical support to the coil and core, as well as toelectrically insulate a coil from its neighboring coil. With thisdesign, induced current will flow from the lumen of one toroid, throughthe tissue and back through the lumen of the other, completing thecircuit within the toroids' conducting medium. A difference between thestructure of the electrode-based stimulator shown in FIG. 5C and themagnetic stimulator shown in FIG. 5D is that the conducting gel ismaintained within the chambers 57 of the electrode-based stimulator,which is generally closed on the back side of the chamber because of thepresence of the electrode 56; but in the magnetic stimulator, the holeof each toroidal core and winding is open, permitting the conducting gelto enter the interconnected chambers 534.

Application of the Stimulators to the Neck of the Patient

Selected nerve fibers are stimulated in different embodiments of methodsthat make use of the disclosed electrical stimulation devices, includingstimulation of the vagus nerve at a location in the patient's neck. Atthat location, the vagus nerve is situated within the carotid sheath,near the carotid artery and the interior jugular vein. The carotidsheath is located at the lateral boundary of the retopharyngeal space oneach side of the neck and deep to the sternocleidomastoid muscle. Theleft vagus nerve is sometimes selected for stimulation becausestimulation of the right vagus nerve may produce undesired effects onthe heart, but depending on the application, the right vagus nerve orboth right and left vagus nerves may be stimulated instead.

The three major structures within the carotid sheath are the commoncarotid artery, the internal jugular vein and the vagus nerve. Thecarotid artery lies medial to the internal jugular vein, and the vagusnerve is situated posteriorly between the two vessels. Typically, thelocation of the carotid sheath or interior jugular vein in a patient(and therefore the location of the vagus nerve) will be ascertained inany manner known in the art, e.g., by feel or ultrasound imaging.Proceeding from the skin of the neck above the sternocleidomastoidmuscle to the vagus nerve, a line may pass successively through thesternocleidomastoid muscle, the carotid sheath and the internal jugularvein, unless the position on the skin is immediately to either side ofthe external jugular vein. In the latter case, the line may passsuccessively through only the sternocleidomastoid muscle and the carotidsheath before encountering the vagus nerve, missing the interior jugularvein. Accordingly, a point on the neck adjacent to the external jugularvein might be preferred for non-invasive stimulation of the vagus nerve.The magnetic stimulator coil may be centered on such a point, at thelevel of about the fifth to sixth cervical vertebra.

FIG. 6 illustrates use of the devices shown in FIGS. 3, 4 and 5 tostimulate the vagus nerve at that location in the neck, in which thestimulator device 50 or 530 in FIG. 5 is shown to be applied to thetarget location on the patient's neck as described above. For reference,FIG. 6A shows the locations of the following vertebrae: first cervicalvertebra 71, the fifth cervical vertebra 75, the sixth cervical vertebra76, and the seventh cervical vertebra 77. FIG. 6B shows the stimulator50 applied to the neck of a child, which is partially immobilized with afoam cervical collar 78 that is similar to ones used for neck injuriesand neck pain. The collar is tightened with a strap 79, and thestimulator is inserted through a hole in the collar to reach the child'sneck surface. As shown, the stimulator is turned on and off with aswitch that is located on the stimulator, and the amplitude ofstimulation may be adjusted with a control knob that is also located onthe stimulator. In other models, the stimulator may be turned on and offremotely, using a wireless controller that may be used to adjust all ofthe stimulation parameters of the controller (on/off, stimulationamplitude, frequency, etc.).

FIG. 7 provides a more detailed view of use of the electricalstimulator, when positioned to stimulate the vagus nerve at the necklocation that is indicated in FIG. 6 . As shown, the stimulator 50 inFIG. 5 touches the neck indirectly, by making electrical contact throughconducting gel 29 (or other conducting material) which may be isdispensed through mesh openings (identified as 51 in FIG. 5 ) of thestimulator or applied as an electrode gel or paste. The layer ofconducting gel 29 in FIG. 7 is shown to connect the device to thepatient's skin, but it is understood that the actual location of the gellayer(s) may be generally determined by the location of mesh 51 shown inFIG. 5 . Furthermore, it is understood that for other embodiments of theinvention, the conductive head of the device may not necessitate the useof additional conductive material being applied to the skin.

The vagus nerve 60 is identified in FIG. 7 , along with the carotidsheath 61 that is identified there in bold peripheral outline. Thecarotid sheath encloses not only the vagus nerve, but also the internaljugular vein 62 and the common carotid artery 63. Features that may beidentified near the surface of the neck include the external jugularvein 64 and the sternocleidomastoid muscle 65. Additional organs in thevicinity of the vagus nerve include the trachea 66, thyroid gland 67,esophagus 68, scalenus anterior muscle 69, and scalenus medius muscle70. The sixth cervical vertebra 76 is also shown in FIG. 7 , with bonystructure indicated by hatching marks.

Methods of treating a patient comprise stimulating the vagus nerve asindicated in FIGS. 6 and 7 , using the electrical stimulation devicesthat are disclosed herein. Stimulation may be performed on the left orright vagus nerve or on both of them simulataneously or alternately. Theposition and angular orientation of the device are adjusted about thatlocation until the patient perceives stimulation when current is passedthrough the stimulator electrodes. The applied current is increasedgradually, first to a level wherein the patient feels sensation from thestimulation. The power is then increased, but is set to a level that isless than one at which the patient first indicates any discomfort.Straps, harnesses, or frames are used to maintain the stimulator inposition. The stimulator signal may have a frequency and otherparameters that are selected to produce a therapeutic result in thepatient. Stimulation parameters for each patient are adjusted on anindividualized basis. Ordinarily, the amplitude of the stimulationsignal is set to the maximum that is comfortable for the patient, andthen the other stimulation parameters are adjusted.

The stimulation is then performed with a sinusoidal burst waveform likethat shown in FIG. 2 . The pattern of a burst followed by silentinter-burst period repeats itself with a period of T. For example, thesinusoidal period □□ may be 200 microseconds; the number of pulses perburst may be N=5; and the whole pattern of burst followed by silentinter-burst period may have a period of T=40000 microseconds, which iscomparable to 25 Hz stimulation. More generally, there may be 1 to 20pulses per burst, preferably five pulses. Each pulse within a burst hasa duration of 1 to 1000 microseconds (i.e., about 1 to 10 KHz),preferably 200 microseconds (about 5 KHz). A burst followed by a silentinter-burst interval repeats at 1 to 5000 bursts per second (bps),preferably at 5-50 bps, and even more preferably 10-25 bps stimulation(10-25 Hz). The preferred shape of each pulse is a full sinusoidal wave,although triangular or other shapes may be used as well. For somepatients, the stimulation may be performed for 30 minutes, and thetreatment is performed several times a week for 12 weeks or longer. Forpatients experiencing intermittent symptoms, the treatment may beperformed only when the patient is symptomatic. However, it isunderstood that parameters of the stimulation protocol may be varied inresponse to heterogeneity in the pathophysiology of patients. Differentstimulation parameters may also be selected as the course of thepatient's disease changes.

In other embodiments of the invention, pairing of vagus nervestimulation may be with a additional sensory stimulation. The pairedsensory stimulation may be bright light, sound, tactile stimulation, orelectrical stimulation of the tongue to simulate odor/taste, e.g.,pulsating with the same frequency as the vagus nerve electricalstimulation. The rationale for paired sensory stimulation is the same assimultaneous, paired stimulation of both left and right vagus nerves,namely, that the pair of signals interacting with one another in thebrain may result in the formation of larger and more coherent neuralensembles than the neural ensembles associated with the individualsignals, thereby enhancing the therapeutic effect.

For example, the hypothalamus is well known to be responsive to thepresence of bright light, so exposing the patient to bright light thatis fluctuating with the same stimulation frequency as the vagus nerve(or a multiple of that frequency) may be performed in an attempt toenhance the role of the hypothalamus in producing the desiredtherapeutic effect. Such paired stimulation does not necessarily relyupon neuronal plasticity and is in that sense different from otherreports of paired stimulation [Navzer D. ENGINEER, Jonathan R. Riley,Jonathan D. Seale, WII A. Vrana, Jai A. Shetake, Sindhu P. Sudanagunta,Michael S. Borland and Michael P. Kilgard. Reversing pathological neuralactivity using targeted plasticity. Nature 470(7332, 2011):101-104;PORTER B A, Khodaparast N, Fayyaz T, Cheung R J, Ahmed S S, Vrana W A,Rennaker R L 2nd, Kilgard M P. Repeatedly pairing vagus nervestimulation with a movement reorganizes primary motor cortex. CerebCortex 22(10, 2012):2365-2374].

Selection of stimulation parameters to preferentially stimulateparticular regions of the brain may be done empirically, wherein a setof stimulation parameters are chosen, and the responsive region of thebrain is measured using fMRI or a related imaging method [CHAE J H,Nahas Z, Lomarev M, Denslow S, Lorberbaum J P, Bohning D E, George M S.A review of functional neuroimaging studies of vagus nerve stimulation(VNS). J Psychiatr Res. 37(6, 2003):443-455; CONWAY C R, Sheline Y I,Chibnall J T, George M S, Fletcher J W, Mintun M A. Cerebral blood flowchanges during vagus nerve stimulation for depression. Psychiatry Res.146(2, 2006):179-84]. Thus, by performing the imaging with differentsets of stimulation parameters, a database may be constructed, such thatthe inverse problem of selecting parameters to match a particular brainregion may be solved by consulting the database.

Stimulation waveforms may also be constructed by superimposing or mixingthe burst waveform shown in FIG. 2 , in which each component of themixture may have a different period T, effectively mixing differentburst-per-second waveforms. The relative amplitude of each component ofthe mixture may be chosen to have a weight according to correlations indifferent bands in an EEG for a particular resting state network. Thus,MANTINI et al performed simultaneous fMRI and EEG measurements and foundthat each resting state network has a particular EEG signature [see FIG.3 in: MANTINI D, Perrucci M G, Del Gratta C, Romani G L, Corbetta M.Electrophysiological signatures of resting state networks in the humanbrain. Proc Natl Acad Sci USA 104(32, 2007):13170-13175]. They reportedrelative correlations in each of the following bands, for each restingstate network that was measured: delta (1-4 Hz), theta (4-8 Hz), alpha(8-13 Hz), beta (13-30 Hz), and gamma (30-50 Hz) rhythms. Forrecently-identified resting state networks, measurement of thecorresponding signature EEG networks will have to be performed.

According to the present embodiment of the invention, multiple signalsshown in FIG. 2 are constructed, with periods T that correspond to alocation near the midpoint of each of the EEG bands (e.g., using theMINATI data, T equals approximately 0.4 sec, 0.1667 sec, 0.095 sec,0.0465 sec, and 0.025 sec, respectively). A more comprehensive mixturecould also be made by mixing more than one signal for each band. Thesesignals are then mixed, with relative amplitudes corresponding to theweights measured for any particular resting state network, and themixture is used to stimulate the vagus nerve of the patient. Phasesbetween the mixed signals are adjusted to optimize the fMRI signal forthe resting state network that is being stimulated, thereby producingentrainment with the resting state network. Stimulation of a network mayactivate or deactivate a network, depending on the detailedconfiguration of adrenergic receptors within the network and their rolesin enhancing or depressing neural activity within the network, as wellas subsequent network-to-network interactions. It is understood thatvariations of this method may be used when different combined fMRI-EEGprocedures are employed and where the same resting state may havedifferent EEG signatures, depending on the circumstances [W U C W, Gu H,Lu H, Stein E A, Chen J H, Yang Y. Frequency specificity of functionalconnectivity in brain networks. Neuroimage 42(3, 2008):1047-1055; LAUFSH. Endogenous brain oscillations and related networks detected bysurface EEG-combined fMRI. Hum Brain Mapp 29(7, 2008):762-769; MUSSO F,Brinkmeyer J, Mobascher A, Warbrick T, Winterer G. Spontaneous brainactivity and EEG microstates. A novel EEG/fMRI analysis approach toexplore resting-state networks. Neuroimage 52(4, 2010):1149-1161;ESPOSITO F, Aragri A, Piccoli T, Tedeschi G, Goebel R, Di Salle F.Distributed analysis of simultaneous EEG-fMRI time-series: modeling andinterpretation issues. Magn Reson Imaging 27(8, 2009):1120-1130; FREYERF, Becker R, Anami K, Curio G, Villringer A, Ritter P.Ultrahigh-frequency EEG during fMRI: pushing the limits ofimaging-artifact correction. Neuroimage 48(1, 2009):94-108]. Once thenetwork is entrained, one may also attempt to change the signature EEGpattern of a network, by slowly changing the frequency content of thestimulation & EEG pattern of the network to which the stimulator isinitially entrained. An objective in this case would be to reduce thefrequency content of the resting state signature EEG.

The individualized selection of parameters for the nerve stimulationprotocol may based on trial and error in order to obtain a beneficialresponse without the sensation of skin pain or muscle twitches.Ordinarily, the amplitude of the stimulation signal is set to themaximum that is comfortable for the patient, and then the otherstimulation parameters are adjusted. Alternatively, the selection ofparameter values may involve tuning as understood in control theory, andas described below. It is understood that parameters may also be variedrandomly in order to simulate normal physiological variability, therebypossibly inducing a beneficial response in the patient [Buchman T G.Nonlinear dynamics, complex systems, and the pathobiology of criticalillness. Curr Opin Crit Care 10(5, 2004):378-82].

Use of Control Theory Methods to Improve Treatment of IndividualPatients

The vagus nerve stimulation may employ methods of control theory (e.g.,feedback) in an attempt to compensate for motion of the stimulatorrelative to the vagus nerve; to avoid potentially dangerous situationssuch as excessive heart rate; to train autonomic control circuits withinthe brain in such a way as to enhance respiratory sinus arrhythmia; andto maintain measured EEG bands (e.g., delta, theta, alpha, beta) withinpredetermined ranges, in attempt to preferentially activate particularresting state networks. Thus, with these methods, the parameters of thevagus nerve stimulation may be changed automatically, depending onphysiological measurements that are made, in attempt to maintain thevalues of the physiological signals within predetermined ranges.

The effects of vagus nerve stimulation on surface EEG waveforms may bedifficult to detect [Michael BEWERNITZ, Georges Ghacibeh, Onur Seref,Panos M. Pardalos, Chang-Chia Liu, and Basim Uthman. Quantification ofthe impact of vagus nerve stimulation parameters onelectroencephalographic measures. AIP Conf. Proc. DATA MINING, SYSTEMSANALYSIS AND OPTIMIZATION IN BIOMEDICINE; Nov. 5, 2007, Volume 953, pp.206-219], but they may exist nevertheless [K00 B. EEG changes with vagusnerve stimulation. J Clin Neurophysiol. 18(5, 2001):434-41; KUBA R,Guzaninová M, Brázdil M, Novák Z, Chrastina J, Rektor I. Effect of vagalnerve stimulation on interictal epileptiform discharges: a scalp EEGstudy. Epilepsia. 43(10, 2002):1181-8; RIZZO P, Beelke M, De Carli F,Canovaro P, Nobili L, Robert A, Fornaro P, Tanganelli P, Regesta G,Ferrillo F. Modifications of sleep EEG induced by chronic vagus nervestimulation in patients affected by refractory epilepsy. ClinNeurophysiol. 115(3, 2004):658-64].

When stimulating the vagus nerve, motion variability may often beattributable to the patient's breathing, which involves contraction andassociated change in geometry of the sternocleidomastoid muscle that issituated close to the vagus nerve (identified as 65 in FIG. 7 ).Modulation of the stimulator amplitude to compensate for thisvariability may be accomplished by measuring the patient's respiratoryphase, or more directly by measuring movement of the stimulator, thenusing controllers (e.g., PID controllers) that are known in the art ofcontrol theory, as now described.

FIG. 8 is a control theory representation of the disclosed vagus nervestimulation methods. As shown there, the autistic child, or the relevantphysiological component of the child, is considered to be the “System”that is to be controlled. The “System” (patient) receives input from the“Environment.” For example, the environment would include ambienttemperature, light, and sound. If the “System” is defined to be only aparticular physiological component of the patient, the “Environment” mayalso be considered to include physiological systems of the patient thatare not included in the “System”. Thus, if some physiological componentcan influence the behavior of another physiological component of thepatient, but not vice versa, the former component could be part of theenvironment and the latter could be part of the system. On the otherhand, if it is intended to control the former component to influence thelatter component, then both components should be considered part of the“System.”

The System also receives input from the “Controller”, which in this casemay comprise the vagus nerve stimulation device, as well as electroniccomponents that may be used to select or set parameters for thestimulation protocol (amplitude, frequency, pulse width, burst number,etc.) or alert the patient as to the need to use or adjust thestimulator (i.e., an alarm). For example, the controller may include thecontrol unit 330 in FIG. 2 . Feedback in the schema shown in FIG. 8 ispossible because physiological measurements of the System are made usingsensors. Thus, the values of variables of the system that could bemeasured define the system's state (“the System Output”). As a practicalmatter, only some of those measurements are actually made, and theyrepresent the “Sensed Physiological Input” to the Controller.

The preferred sensors will include ones ordinarily used for ambulatorymonitoring. For example, the sensors may comprise those used inconventional Holter and bedside monitoring applications, for monitoringheart rate and variability, ECG, respiration depth and rate, coretemperature, hydration, blood pressure, brain function, oxygenation,skin impedance, and skin temperature. The sensors may be embedded ingarments or placed in sports wristwatches, as currently used in programsthat monitor the physiological status of soldiers [G. A. SHAW, A. M.Siegel, G. Zogbi, and T. P. Opar. Warfighter physiological andenvironmental monitoring: a study for the U.S. Army Research Institutein Environmental Medicine and the Soldier Systems Center. MIT LincolnLaboratory, Lexington Mass. 1 Nov. 2004, pp. 1-141]. The ECG sensorsshould be adapted to the automatic extraction and analysis of particularfeatures of the ECG, for example, indices of P-wave morphology, as wellas heart rate variability indices of parasympathetic and sympathetictone. Measurement of respiration using noninvasive inductiveplethysmography, mercury in silastic strain gauges or impedancepneumography is particularly advised, in order to account for theeffects of respiration on the heart. A noninvasive accelerometer mayalso be included among the ambulatory sensors, in order to identifymotion artifacts. An event marker may also be included in order for thepatient to mark relevant circumstances and sensations.

For brain monitoring, the sensors may comprise ambulatory EEG sensors[CASSON A, Yates D, Smith S, Duncan J, Rodriguez-Villegas E. Wearableelectroencephalography. What is it, why is it needed, and what does itentail? IEEE Eng Med Biol Mag. 29(3, 2010):44-56] or optical topographysystems for mapping prefrontal cortex activation [Atsumori H, Kiguchi M,Obata A, Sato H, Katura T, Funane T, Maki A. Development of wearableoptical topography system for mapping the prefrontal cortex activation.Rev Sci Instrum. 2009 April; 80(4):043704]. Signal processing methods,comprising not only the application of conventional linear filters tothe raw EEG data, but also the nearly real-time extraction of non-linearsignal features from the data, may be considered to be a part of the EEGmonitoring [D. Puthankattil SUBHA, Paul K. Joseph, Rajendra Acharya U,and Choo Min Lim. EEG signal analysis: A survey. J Med Syst34(2010):195-212]. In the present application, the features wouldinclude EEG bands (e.g., delta, theta, alpha, beta).

Detection of the phase of respiration may be performed non-invasively byadhering a thermistor or thermocouple probe to the patient's cheek so asto position the probe at the nasal orifice. Strain gauge signals frombelts strapped around the chest, as well as inductive plethysmographyand impedance pneumography, are also used traditionally tonon-invasively generate a signal that rises and falls as a function ofthe phase of respiration. Respiratory phase may also be inferred frommovement of the sternocleidomastoid muscle that also causes movement ofthe vagus nerve stimulator during breathing, measured usingaccelerometers attached to the vagus nerve stimulator, as describedbelow. After digitizing such signals, the phase of respiration may bedetermined using software such as “puka”, which is part ofPhysioToolkit, a large published library of open source software anduser manuals that are used to process and display a wide range ofphysiological signals [GOLDBERGER A L, Amaral LAN, Glass L, Hausdorff JM, Ivanov PCh, Mark R G, Mietus J E, Moody G B, Peng C K, Stanley H E.PhysioBank, PhysioToolkit, and PhysioNet: Components of a New ResearchResource for Complex Physiologic Signals. Circulation 101(23,2000):e215-e220] available from PhysioNet, M.I.T. Room E25-505A, 77Massachusetts Avenue, Cambridge, Mass. 02139]. In one embodiment of thepresent invention, the control unit 330 contains an analog-to-digitalconverter to receive such analog respiratory signals, and software forthe analysis of the digitized respiratory waveform resides within thecontrol unit 330. That software extracts turning points within therespiratory waveform, such as end-expiration and end-inspiration, andforecasts future turning-points, based upon the frequency with whichwaveforms from previous breaths match a partial waveform for the currentbreath. The control unit 330 then controls the impulse generator 310,for example, to stimulate the selected nerve only during a selectedphase of respiration, such as all of inspiration or only the firstsecond of inspiration, or only the expected middle half of inspiration.

It may be therapeutically advantageous to program the control unit 330to control the impulse generator 310 in such a way as to temporallymodulate stimulation by the magnetic stimulator coils or electrodes,depending on the phase of the patient's respiration. In patentapplication JP2008/081479A, entitled Vagus nerve stimulation system, toYOSHIHOTO, a system is also described for keeping the heart rate withinsafe limits. When the heart rate is too high, that system stimulates apatient's vagus nerve, and when the heart rate is too low, that systemtries to achieve stabilization of the heart rate by stimulating theheart itself, rather than use different parameters to stimulate thevagus nerve. In that disclosure, vagal stimulation uses an electrode,which is described as either a surface electrode applied to the bodysurface or an electrode introduced to the vicinity of the vagus nervevia a hypodermic needle. That disclosure is unrelated to theneurodevelopmental problems that are addressed here, but it doesconsider stimulation during particular phases of the respiratory cycle,for the following reason. Because the vagus nerve is near the phrenicnerve, Yoshihoto indicates that the phrenic nerve will sometimes beelectrically stimulated along with the vagus nerve. The presentapplicants have not experienced this problem, so the problem may be oneof a misplaced electrode. In any case, the phrenic nerve controlsmuscular movement of the diaphragm, so consequently, stimulation of thephrenic nerve causes the patient to hiccup or experience irregularmovement of the diaphragm, or otherwise experience discomfort. Tominimize the effects of irregular diaphragm movement, Yoshihoto's systemis designed to stimulate the phrenic nerve (and possibly co-stimulatethe vagus nerve) only during the inspiration phase of the respiratorycycle and not during expiration. Furthermore, the system is designed togradually increase and then decrease the magnitude of the electricalstimulation during inspiration (notably amplitude and stimulus rate) soas to make stimulation of the phrenic nerve and diaphragm gradual.

The present invention also discloses stimulation of the vagus nerve as afunction of respiratory phase, but the timing, amplitude and rationalefor the stimulation are all different from Yoshihoto's method. Thepresent objective of varying the electrical nerve stimulation as afunction of respiratory phase is to train the autonomic nervous systemof the autistic child, in such a way as to enhance respiratory sinusarrhythmia (RSA). During the process of RSA, inhalation temporarilysuppresses vagal activity, causing an immediate increase in heart rate.Exhalation then decreases heart rate and causes vagal activity toresume. The magnitude of RSA is readily measured by extracting heartrate from the ECG of the patient, decomposing the heart rate into itsFourier components, and measuring the peak or frequency range that isexaggerated by respiration [U. Rajendra ACHARYA, K. Paul Joseph, N.Kannathal, Choo Min Lim and Jasjit S. Suri. Heart rate variability: areview. Medical and Biological Engineering and Computing 44(12, 2006),1031-1051; YASUMA F, Hayano J. Respiratory sinus arrhythmia: why doesthe heartbeat synchronize with respiratory rhythm? Chest 125(2,2004):683-690; BERNTSON G G, Cacioppo J T, Quigley K S. Respiratorysinus arrhythmia: autonomic origins, physiological mechanisms, andpsychophysiological implications. Psychophysiology 30(2,1993):183-196].The RSA is an indication of vagal or parasympathetic tone. In contrast,sympathetic tone may be estimated from lower frequency components of theFourier spectrum, or by measuring electrodermal activity [WolframBOUCSEIN. Electrodermal activity, 2nd Ed., New York: Springer, 2012, pp.1-618].

Early in gestation, the fetal heart rate is predominately under thecontrol of the sympathetic nervous system and arterial chemoreceptors.As the fetus develops, its heart rate decreases in response toparasympathetic (vagal) nervous system maturation. RSA then develops,which may be measured even in utero during fetal breathing episodes[DIVON M Y Yeh S Y, Zimmer E Z, Platt L D, Paldi E, Paul R H.Respiratory sinus arrhythmia in the human fetus. Am J Obstet Gynecol151(4,1985):425-428]. Thereafter, RSA follows a maturational trajectorythat parallels changes in both number and ratio of myelinated vagalfibers.

Children with autism do not follow the normal changing pattern ofsympathetic/parasympathetic balance, and they have significantly reducedparasympathetic tone with autonomic dysfunction, as evidenced by theirreduced RSA [BAL E, Harden E, Lamb D, Van Hecke A V, Denver J W, PorgesS W. Emotion recognition in children with autism spectrum disorders:relations to eye gaze and autonomic state. J Autism Dev Disord 40(3,2010):358-370; SCHAAF R C, Miller L J, Seawell D, O'Keefe S. Childrenwith disturbances in sensory processing: a pilot study examining therole of the parasympathetic nervous system. Am J Occup Ther 57(4,2003):442-449; X. MING, P. O. O. Julu, M. Brimacombe, S. Connor, and M.L. Daniels, Reduced cardiac parasympathetic activity in children withautism. Brain and Development 27(7, 2005):509-516]. The balance ofexcitatory and inhibitory activity within the sympathetic andparasympathetic divisions of the autonomic nervous system in autisticchildren may also be measured using pupil diameter as a surrogate[ANDERSON C J, Colombo J. Larger tonic pupil size in young children withautism spectrum disorder. Dev Psychobiol 51(2, 2009):207-211]. Comparedwith normal children, autistic children have an imbalance that favorssympathetic tone, and they apparently use self-stimulation activities inorder to calm hyper-responsive activity of their sympatheic nervoussystem [W HIRSTEIN, P Iversen, and V S Ramachandran. Autonomic responsesof autistic children to people and objects. Proc Royal Soc. Biol Sci.268(1479, 2001): 1883-1888].

The present invention attempts to increase parasympathetic tone inautistic children, by increasing their RSA. It does so by training thechild's autonomic nervous system to inhibit or suppress vagal activityduring inhalation and increase vagal activity during exhalation. Thus, ablocking or inhibiting electrical signal is applied preferably to theright vagus nerve during inhalation (or not stimulated at all in oneembodiment), but it is stimulated with an excitatory signal duringexhalation. The signals may increase in amplitude gradually to a maximumat the midpoint of exhalation or inhalation, and then decrease, so as tosimulate what the vagus nerve would be doing in normal RSA. Assumingthat abnormal RSA has already been documented for the child in utero andshortly after birth, the intervention is preferably performed during thechild's first and second years when the vagus nerve and autonomicnervous system are still rapidly developing and most susceptible toexcitation/inhibition balancing by external influences [DORRNAL, Yuan K,Barker A J, Schreiner C E, Froemke R C. Developmental sensory experiencebalances cortical excitation and inhibition. Nature 465(7300,2010):932-936]. Even if the intervention is not performed during thechild's first two years, it may still be effective in increasing RSAowing to the plasticity of neural circuits, as illustrated by vagalnerve stimulation treatments for tinnitus and movement disorders [NavzerD. ENGINEER, Jonathan R. Riley, Jonathan D. Seale, WII A. Vrana, Jai A.Shetake, Sindhu P. Sudanagunta, Michael S. Borland and Michael P.Kilgard. Reversing pathological neural activity using targetedplasticity. Nature 470(7332, 2011):101-104; PORTER B A, Khodaparast N,Fayyaz T, Cheung R J, Ahmed S S, Vrana W A, Rennaker R L 2nd, Kilgard MP. Repeatedly pairing vagus nerve stimulation with a movementreorganizes primary motor cortex. Cereb Cortex 22(10, 2012):2365-2374].The treatment may be performed for an extended period every day, andover the course of many weeks, the amplitudes of the stimulation may bereduced as the child's autonomic nervous system develops a more normalRSA.

In some embodiments of the invention, overheating of the magneticstimulator coil may also be minimized by optionally restricting themagnetic stimulation to particular phases of the respiratory cycle,allowing the coil to cool during the other phases of the respiratorycycle. Alternatively, greater peak power may be achieved per respiratorycycle by concentrating all the energy of the magnetic pulses intoselected phases of the respiratory cycle.

Furthermore, as an option in the present invention, parameters of thestimulation may be modulated by the control unit 330 to control theimpulse generator 310 in such a way as to temporally modulatestimulation by the magnetic stimulator coil or electrodes, so as toachieve and maintain the heart rate within safe or desired limits. Inthat case, the parameters of the stimulation are individually raised orlowered in increments (power, frequency, etc.), and the effect as anincreased, unchanged, or decreased heart rate is stored in the memory ofthe control unit 330. When the heart rate changes to a value outside thespecified range, the control unit 330 automatically resets theparameters to values that had been recorded to produce a heart ratewithin that range, or if no heart rate within that range has yet beenachieved, it increases or decreases parameter values in the directionthat previously acquired data indicate would change the heart rate inthe direction towards a heart rate in the desired range. Similarly, thearterial blood pressure is also recorded non-invasively in an embodimentof the invention, and as described above, the control unit 330 extractsthe systolic, diastolic, and mean arterial blood pressure from the bloodpressure waveform. The control unit 330 will then control the impulsegenerator 310 in such a way as to temporally modulate nerve stimulationby the magnetic stimulator coil or electrodes, in such a way as toachieve and maintain the blood pressure within predetermined safe ordesired limits, by the same method that was indicated above for theheart rate. Thus, even if one does not intend to treat neurodevelpmentalproblems, embodiments of the invention described above may be used toachieve and maintain the heart rate and blood pressure within desiredranges.

Let the measured output variables of the system in FIG. 8 be denoted byy_(i) (i=1 to Q); let the desired (reference or setpoint) values ofy_(i) be denoted by r_(i) and let the controller's input to the systemconsist of variables u_(j) (j=1 to P). The objective is for a controllerto select the input u_(j) in such a way that the output variables (or asubset of them) closely follows the reference signals r_(i), i.e., thecontrol error e_(i)=r_(i)−y_(i) is small, even if there is environmentalinput or noise to the system. Consider the error functione_(i)=r_(i)−y_(i) to be the sensed physiological input to the controllerin FIG. 8 (i.e., the reference signals are integral to the controller,which subtracts the measured system values from them to construct thecontrol error signal). The controller will also receive a set ofmeasured environmental signals v_(k) (k=1 to R), which also act upon thesystem as shown in FIG. 8 .

The functional form of the system's input u(t) is constrained to be asshown in FIGS. 2D and 2E. Ordinarily, a parameter that needs adjustingis the one associated with the amplitude of the signal shown in FIG. 2 .As a first example of the use of feedback to control the system,consider the problem of adjusting the input u(t) from the vagus nervestimulator (i.e., output from the controller) in order to compensate formotion artifacts.

Nerve activation is generally a function of the second spatialderivative of the extracellular potential along the nerve's axon, whichwould be changing as the position of the stimulator varies relative tothe axon [F. RATTAY. The basic mechanism for the electrical stimulationof the nervous system. Neuroscience 89 (2, 1999):335-346]. Such motionartifact can be due to movement by the patient (e.g., neck movement) ormovement within the patient (e.g. sternocleidomastoid muscle contractionassociated with respiration), or it can be due to movement of thestimulator relative to the body (slippage or drift). Thus, one expectsthat because of such undesired or unavoidable motion, there will usuallybe some error (e=r−y) in the intended (r) versus actual (y) nervestimulation amplitude that needs continuous adjustment.

Accelerometers can be used to detect all these types of movement, usingfor example, Model LSM330DL from STMicroelectronics, 750 Canyon Dr # 300Coppell, Tex. 75019. One or more accelerometer is attached to thepatient's neck, and one or more accelerometer is attached to the head ofthe stimulator in the vicinity of where the stimulator contacts thepatient. Because the temporally integrated outputs of the accelerometersprovide a measurement of the current position of each accelerometer, thecombined accelerometer outputs make it possible to measure any movementof the stimulator relative to the underlying tissue.

The location of the vagus nerve underlying the stimulator may bedetermined preliminarily by placing an ultrasound probe at the locationwhere the center of the stimulator will be placed [KNAPPERTZ V A,Tegeler C H, Hardin S J, McKinney W M. Vagus nerve imaging withultrasound: anatomic and in vivo validation. Otolaryngol Head Neck Surg118(1,1998):82-5]. The ultrasound probe is configured to have the sameshape as the stimulator, including the attachment of one or moreaccelerometer. As part of the preliminary protocol, the patient withaccelerometers attached is then instructed or helped to perform neckmovements, breathe deeply so as to contract the sternocleidomastoidmuscle, and generally simulate possible motion that may accompanyprolonged stimulation with the stimulator. This would include possibleslippage or movement of the stimulator relative to an initial positionon the patient's neck. While these movements are being performed, theaccelerometers are acquiring position information, and the correspondinglocation of the vagus nerve is determined from the ultrasound image.With these preliminary data, it is then possible to infer the locationof the vagus nerve relative to the stimulator, given only theaccelerometer data during a stimulation session, by interpolatingbetween the previously acquired vagus nerve position data as a functionof accelerometer position data.

For any given position of the stimulator relative to the vagus nerve, itis also possible to infer the amplitude of the electric field that itproduces in the vicinity of the vagus nerve. This is done by calculationor by measuring the electric field that is produced by the stimulator asa function of depth and position within a phantom that simulates therelevant bodily tissue [Francis Marion MOORE. Electrical Stimulation forpain suppression: mathematical and physical models. Thesis, School ofEngineering, Cornell University, 2007; Bartosz SAWICKI, Robert Szmurło,Przemysław Płonecki, Jacek Starzyński, Stanisław Wincenciak, AndrzejRysz. Mathematical Modelling of Vagus Nerve Stimulation. pp. 92-97 in:Krawczyk, A. Electromagnetic Field, Health and Environment: Proceedingsof EHE'07. Amsterdam, IOS Press, 2008]. Thus, in order to compensate formovement, the controller may increase or decrease the amplitude of theoutput from the stimulator (u) in proportion to the inferred deviationof the amplitude of the electric field in the vicinity of the vagusnerve, relative to its desired value.

For present purposes, no distinction is made between a system outputvariable and a variable representing the state of the system. Then, astate-space representation, or model, of the system consists of a set offirst order differential equations of the form dy_(i)/dt=F_(i)(t_(i){y_(i)},{u_(i)},{v_(k)}; {r_(i)}), where t is timeand where in general, the rate of change of each variable y_(i) is afunction (F_(i)) of many other output variables as well as the input andenvironmental signals.

Classical control theory is concerned with situations in which thefunctional form of F_(i) is as a linear combination of the state andinput variables, but in which coefficients of the linear terms are notnecessarily known in advance. In this linear case, the differentialequations may be solved with linear transform (e.g., Laplace transform)methods, which convert the differential equations into algebraicequations for straightforward solution. Thus, for example, asingle-input single-output system (dropping the subscripts on variables)may have input from a controller of the form:

${u(t)} = {{K_{p}{e(t)}} + {K_{i}{\int_{0}^{t}{{e(\tau)}d\;\tau}}} + {K_{d}\frac{de}{dt}}}$where the parameters for the controller are the proportional gain(K_(p)), the integral gain (K_(i)) and the derivative gain (K_(d)). Thistype of controller, which forms a controlling input signal with feedbackusing the error e=r−y, is known as a PID controller(proportional-integral-derivative).

Optimal selection of the parameters of the controller could be throughcalculation, if the coefficients of the corresponding state differentialequation were known in advance. However, they are ordinarily not known,so selection of the controller parameters (tuning) is accomplished byexperiments in which the error e either is or is not used to form thesystem input (respectively, closed loop or open loop experiments). In anopen loop experiment, the input is increased in a step (or random binarysequence of steps), and the system response is measured. In a closedloop experiment, the integral and derivative gains are set to zero, theproportional gain is increased until the system starts to oscillate, andthe period of oscillation is measured. Depending on whether theexperiment is open or closed loop, the selection of PID parameter valuesmay then be selected according to rules that were described initially byZiegler and Nichols. There are also many improved versions of tuningrules, including some that can be implemented automatically by thecontroller [LI, Y., Ang, K. H. and Chong, G. C. Y. Patents, software andhardware for PID control: an overview and analysis of the current art.IEEE Control Systems Magazine, 26 (1, 2006): 42-54; Karl Johan Aström &Richard M. Murray. Feedback Systems: An Introduction for Scientists andEngineers. Princeton N.J.: Princeton University Press, 2008; FinnHAUGEN. Tuning of PID controllers (Chapter 10) In: Basic Dynamics andControl. 2009. ISBN 978-82-91748-13-9. TechTeach, Enggravhøgda 45,N-3711 Skien, Norway. http://techteach.no., pp. 129-155; Dingyu XUE,YangQuan Chen, Derek P. Atherton. PID controller design (Chapter 6), In:Linear Feedback Control: Analysis and Design with MATLAB. Society forIndustrial and Applied Mathematics (SIAM).3600 Market Street, 6thFloor,Philadelphia, Pa. (2007), pp. 183-235; Jan JANTZEN, Tuning OfFuzzy PID Controllers, Technical University of Denmark, report 98-H 871,Sep. 30, 1998].

Commercial versions of PID controllers are available, and they are usedin 90% of all control applications. To use such a controller, forexample, in an attempt to maintain the EEG gamma band at a particularlevel relative to the alpha band, one could set the integral andderivative gains to zero, increase the proportional gain (amplitude ofthe stimulation) until the relative gamma band level starts tooscillate, and then measure the period of oscillation. The PID wouldthen be set to its tuned parameter values.

Although classical control theory works well for linear systems havingone or only a few system variables, special methods have been developedfor systems in which the system is nonlinear (i.e., the state-spacerepresentation contains nonlinear differential equations), or multipleinput/output variables. Such methods are important for the presentinvention because the physiological system to be controlled will begenerally nonlinear, and there will generally be multiple outputphysiological signals. It is understood that those methods may also beimplemented in the controller shown in FIG. 8 [Torkel GLAD and LennartLjung. Control Theory. Multivariable and Nonlinear Methods. New York:Taylor and Francis, 2000; Zdzislaw BUBNICKI. Modern Control Theory.Berlin: Springer, 2005].

The controller shown in FIG. 8 may also make use of feed-forward methods[Coleman BROSILOW, Babu Joseph. Feedforward Control (Chapter 9) In:Techniques of Model-Based Control. Upper Saddle River, N.J.: PrenticeHall PTR, 2002. pp, 221-240]. Thus, the controller in FIG. 8 may be atype of predictive controller, methods for which have been developed inother contexts as well, such as when a model of the system is used tocalculate future outputs of the system, with the objective of choosingamong possible inputs so as to optimize a criterion that is based onfuture values of the system's output variables.

Performance of system control can be improved by combining the feedbackclosed-loop control of a PID controller with feed-forward control,wherein knowledge about the system's future behavior can be fed forwardand combined with the PID output to improve the overall systemperformance. For example, if the sensed environmental input in FIG. 8 issuch the environmental input to the system will have a deleteriouseffect on the system after a delay, the controller may use thisinformation to provide anticipatory control input to the system, so asto avert or mitigate the deleterious effects that would have been sensedonly after-the-fact with a feedback-only controller.

A mathematical model of the system is needed in order to perform thepredictions of system behavior, e.g., make predictions concerning thechild's future respiratory state. For example, if the vagus nervestimulation is intended to increase only until the middle of inspirationor expiration, one would ordinarily know only after-the-fact whether themidpoint has actually been reached. Models that are completely basedupon physical first principles (white-box) are rare, especially in thecase of physiological systems. Instead, most models that make use ofprior structural and mechanistic understanding of the system areso-called grey-box models. If the mechanisms of the systems are notsufficiently understood in order to construct a white or grey box model,a black-box model may be used instead. One example for the problem ofpredicting respiratory phase is described by CAMINAL and colleagues[CAMINAL P, Domingo L, Giraldo B F, Vallverdú M, Benito S, Vazquez G,Kaplan D. Variability analysis of the respiratory volume based onnon-linear prediction methods. Med Biol Eng Comput 42(1, 2004):86-91].Such black box models comprise autoregressive models [Tim BOLLERSLEV.Generalized autoregressive condiditional heteroskedasticity. Journal ofEconometrics 31(1986):307-327], or those that make use of principalcomponents [James H. STOCK, Mark W. Watson. Forecasting with ManyPredictors, In: Handbook of Economic Forecasting. Volume 1, G. Elliott,C. W. J. Granger and A. Timmermann,eds (2006) Amsterdam: Elsevier B. V,pp 515-554], Kalman filters [Eric A. WAN and Rudolph van der Merwe. Theunscented Kalman filter for nonlinear estimation, In: Proceedings ofSymposium 2000 on Adaptive Systems for Signal Processing, Communicationand Control (AS-SPCC), IEEE, Lake Louise, Alberta, Canada, October,2000, pp 153-158], wavelet transforms [O. RENAUD, J.-L. Stark, F.Murtagh. Wavelet-based forecasting of short and long memory time series.Signal Processing 48(1996):51-65], hidden Markov models [Sam ROWEIS andZoubin Ghahramani. A Unifying Review of Linear Gaussian Models. NeuralComputation 11(2, 1999): 305-345], or artificial neural networks[Guoquiang ZHANG, B. Eddy Patuwo, Michael Y. Hu. Forecasting withartificial neural networks: the state of the art. International Journalof Forecasting 14(1998): 35-62].

For the present invention, if a black-box model must be used, thepreferred model will be one that makes use of support vector machines. Asupport vector machine (SVM) is an algorithmic approach to the problemof classification within the larger context of supervised learning. Anumber of classification problems whose solutions in the past have beensolved by multi-layer back-propagation neural networks, or morecomplicated methods, have been found to be more easily solvable by SVMs[Christopher J. C. BURGES. A tutorial on support vector machines forpattern recognition. Data Mining and Knowledge Discovery 2(1998),121-167; J. A. K. SUYKENS, J. Vandewalle, B. De Moor. Optimal Control byLeast Squares Support Vector Machines. Neural Networks 14 (2001):23-35;SAPANKEVYCH, N. and Sankar, R. Time Series Prediction Using SupportVector Machines: A Survey. IEEE Computational Intelligence Magazine 4(2,2009): 24-38; PRESS, W H; Teukolsky, S A; Vetterling, W T; Flannery, B P(2007). Section 16.5. Support Vector Machines. In: Numerical Recipes:The Art of Scientific Computing (3rd ed.). New York: CambridgeUniversity Press].

As a final example, consider the problem of predicting and preventingrepetitive behavior on the part of an autistic child, particularly motorstereotypies (e.g., hand flapping, or rocking and swinging). As notedabove, PORGES suggests that such behaviors in autistic individuals mayreflect a naturally occurring biobehavioral strategy to stimulate andregulate a vagal system that is not functioning efficiently. If that istrue, it may be possible to predict the imminence of such behavior frommeasurement of physiological variables of the child and avert thebehavior by altering physiological variables of the child. The exampleassumes that vagus nerve stimulation can be applied as described abovein connection with enhancing RSA, but the stimulation is applied onlywhen the invention's feedforward system predicts that such repetitivebehavior is imminent.

A training set of physiological data will have been acquired thatincludes whether or not the child is exhibiting the repetitive behavior.Thus, the classification of the child's state is whether or not thebehavior is present, and the data used to make the classificationconsist of acquired physiological data. In general the morephysiological data that are acquired, the better the forecast will be.At a minimum, the physiological variables should include heart rate(electrocardiogram leads), respiration (e.g., abdominal and thoracicplethysmography), and motion (accelerometer). Preferably it would alsoinclude skin impedance (electrodermal leads), carbon dioxide (capnometrywith nasual cannula), vocalization (microphones), light (light sensor),external and finger temperature (thermometers), EEG and its derivedfeatures; etc., as well as parameters of the stimulator device, allevaluated at D time units prior to the time at which binary “repetitivebehavior present” (yes/no) data are acquired, as indicated by acaregiver. Thus, for a child who is experiencing repetitive behavior,the SVM is trained to forecast the termination of the behavior, A timeunits into the future, and the training set includes the time-course offeatures extracted from the above-mentioned physiological signals. For achild who is not experiencing repetitive behavior, the SVM is trained toforecast the imminence of repetitive behavior, A time units into thefuture, and the training set includes the above-mentioned physiologicalsignals. After training the SVM, it is implemented as part of thecontroller. For children who are not experiencing symptoms, thecontroller may apply the RSA vagal nerve stimulation as a prophylacticwhenever there is a forecast of imminent repetitive behavior. Thecontroller will also turn off the RSA vagal nerve stimulation when itforecasts or detects the termination of the repetitive behavior.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

What is claimed is:
 1. A device for treating or preventing a behavioraldisorder in a patient, comprising: a housing having a contact surfacefor contacting an outer skin surface of the of a neck of a patient; apower source within the housing; and wherein the power source generatesand transmits an electric current through the contact surface and theouter skin surface of the neck to a vagus nerve within the patientnon-invasively to generate an electrical impulse at the vagus nerve,wherein the electrical impulse is sufficient to modify the behavioraldisorder in the patient, wherein the electrical impulse comprises burstsof about 2 to about 20 pulses with a silent intra-burst interval betweeneach burst and wherein each burst has a frequency of about 1 to about100 bursts per second.
 2. The device of claim 1 further comprising anelectrode within the housing coupled to the contact surface.
 3. Thedevice of claim 2 further comprising a conductor within the housingcoupled to the electrode and the power source, wherein the power sourcegenerates and transmits the electric current through the conductor,electrode and the contact surface to the vagus nerve.
 4. The device ofclaim 2 wherein the power source comprises a signal generator coupled tothe electrode within the housing.
 5. The device of claim 3 wherein theconductor is a first conductor, the device further comprising a secondconductor coupling the electrode to the contact surface.
 6. The deviceof claim 5 wherein the second conductor comprises an electricallyconductive fluid within the housing between the electrode and thecontact surface.
 7. The device of claim 6 wherein the electricallyconductive fluid comprises an electrically conductive gel.
 8. The deviceof claim 1 wherein each pulse is about 50 to 1000 microseconds induration.
 9. The device of claim 1 the electrical current generates anelectric field at the vagus nerve above a threshold for generatingaction potentials within A and B fibers of the vagus nerve and below athreshold for generating action potentials within C fibers of the vagusnerve.
 10. The device of claim 1 wherein the electrical currentgenerates an electric field at the vagus nerve above a threshold forgenerating action potentials within fibers of the vagus nerveresponsible for activating neural pathways causing release of inhibitoryneurotransmitters within a brain of the patient.
 11. The device of claim10 wherein the inhibitory neurotransmitters comprise GABA,norepinephrine, or serotonin.
 12. The device of claim 1 wherein thebehavioral disorder comprises attention-deficit hyperactivity disorder(ADHD).
 13. The device of claim 1 wherein the behavioral disordercomprises an autism spectrum disorder.
 14. The device of claim 1 whereinthe behavioral disorder comprises Asperger syndrome.